Advertisement

Effect of Physiotherapeutic Interventions on Biomarkers of Neuropathic Pain: A Systematic Review of Preclinical Literature

  • Luis Matesanz-García
    Affiliations
    Escuela Internacional de Doctorado, Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, Alcorcón, Spain

    Departamento de Fisioterapia, Centro Superior de Estudios Universitarios La Salle, Universidad Autónoma de Madrid, Madrid, Spain
    Search for articles by this author
  • Annina B. Schmid
    Affiliations
    Nuffield Department for Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
    Search for articles by this author
  • Julio Eduardo Cáceres-Pajuelo
    Affiliations
    Kapalua Fisioterapia S.L., Madrid, Spain
    Search for articles by this author
  • Ferran Cuenca-Martínez
    Correspondence
    Address reprint requests to Ferran Cuenca-Martínez, Department of Physiotherapy, University of Valencia, 46010 Valencia, Spain.
    Affiliations
    Exercise Intervention for Health Research Group (EXINH-RG), Department of Physiotherapy, University of Valencia, Valencia, Spain
    Search for articles by this author
  • Alberto Arribas-Romano
    Affiliations
    Escuela Internacional de Doctorado, Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, Alcorcón, Spain

    Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Rey Juan Carlos University, Madrid, Spain
    Search for articles by this author
  • Yeray González-Zamorano
    Affiliations
    Escuela Internacional de Doctorado, Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, Alcorcón, Spain

    Grupo de Investigación de Neurorrehabilitación del Daño Cerebral y los Trastornos del Movimiento (GINDAT), Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain
    Search for articles by this author
  • Carlos Goicoechea-García
    Affiliations
    Departament Basic Health Sciences Rey Juan Carlos University, Madrid, Spain
    Search for articles by this author
  • Josué Fernández-Carnero
    Affiliations
    Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Rey Juan Carlos University, Madrid, Spain

    Grupo de Investigación de Neurorrehabilitación del Daño Cerebral y los Trastornos del Movimiento (GINDAT), Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain

    Motion in Brains Research Group, Institute of Neuroscience and Sciences of the Movement (INCIMOV), Centro Superior de Estudios Universitarios La Salle, Universidad Autónoma de Madrid, Madrid, Spain

    Grupo Multidisciplinar de Investigación y Tratamiento del Dolor, Grupo de Excelencia Investigadora URJC-Banco de Santander, Madrid, Spain

    La Paz Hospital Institute for Health Research, IdiPAZ, Madrid, Spain
    Search for articles by this author
Open AccessPublished:June 26, 2022DOI:https://doi.org/10.1016/j.jpain.2022.06.007

      Highlights

      • Physiotherapy can modulate biomarkers of neuropathic pain in different areas of the nervous system.
      • Exercise and electro-acupuncture have most evidence for neuropathic pain biomarker modulation.
      • Physiotherapy may influence the neuro-immune system by downregulating pronociceptive biomarkers.
      • However, high risk of bias and heterogeneity in most studies prevent firm conclusions.

      Abstract

      The purpose of this systematic review was to evaluate the effects of physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain (PNP). The search was performed in Pubmed, Web of Science, EMBASE, Cochrane, Cinhal, Psycinfo, Scopus, Medline, and Science Direct. Studies evaluating any type of physiotherapy intervention for PNP (systemic or traumatic) were included. Eighty-one articles were included in this review. The most common PNP model was chronic constriction injury, and the most frequently studied biomarkers were related to neuro-immune processes. Exercise therapy and Electro-acupuncture were the 2 most frequently studied physiotherapy interventions while acupuncture and joint mobilization were less frequently examined. Most physiotherapeutic interventions modulated the expression of biomarkers related to neuropathic pain. Whereas the results seem promising; they have to be considered with caution due to the high risk of bias of included studies and high heterogeneity of the type and anatomical localization of biomarkers reported. The review protocol is registered on PROSPERO (CRD42019142878).

      Perspective

      This article presents the current evidence about physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain. Existing findings are reviewed, and relevant data are provided on the effectiveness of each physiotherapeutic modality, as well as its certainty of evidence and clinical applicability.

      Key words

      Introduction

      Neuropathic pain (NP) is defined as pain caused by a lesion or a disease of the somatosensory system
      • Treede R-D
      • Jensen TS
      • Campbell JN
      • Cruccu G
      • Dostrovsky JO
      • Griffin JW
      • Hansson P
      • Hughes R
      • Nurmikko T
      • Serra J
      Neuropathic pain: redefinition and a grading system for clinical and research purposes.
      and is estimated to affect between 6.9 and 10% of the general population.
      • Van Hecke O
      • Austin SK
      • Khan RA
      • Smith BH
      • Torrance N
      Neuropathic pain in the general population: A systematic review of epidemiological studies.
      ,
      • Smith BH
      • Hébert HL
      • Veluchamy A
      Neuropathic pain in the community: prevalence, impact, and risk factors.
      Peripheral neuropathic pain is becoming more prevalent due to an aging world population, the rising impact of diabetes mellitus as well as higher survival rates of cancer and the implications of chemotherapy.
      • Colloca L
      • Ludman T
      • Bouhassira D
      • Baron R
      • Dickenson AH
      • Yarnitsky D
      • Freeman R
      • Truini A
      • Attal N
      • Finnerup NB
      • Eccleston C
      • Kalso E
      • Bennett DL
      • Dworkin RH
      • Raja SN
      Neuropathic pain.
      Management of NP remains challenging, as many patients do not experience adequate pain relief.

      Connor ABO, Dworkin RH: Treatment of neuropathic pain: An overview of recent guidelines 122:S22–32, 2009.

      ,
      • O´connor AlecB
      Neuropathic pain quality of life impact, costs and const effectivenes of Therapy.
      ,
      • O'Connor AB
      Neuropathic pain.
      ,
      • O'Connor AB
      • Dworkin RH
      Treatment of neuropathic pain: An overview of recent guidelines.
      Treatment of neuropathic pain usually focuses on symptom management.
      • Cobianchi S
      • Casals-Diaz L
      • Jaramillo J
      • Navarro X
      Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury.
      Nonsurgical interventions are recommended as first-line treatments for patients with neuropathic pain.
      • Haanpää M
      • Attal N
      • Backonja M
      • Baron R
      • Bennett M
      • Bouhassira D
      • Cruccu G
      • Hansson P
      • Haythornthwaite JA
      • Iannetti GD
      • Jensen TS
      • Kauppila T
      • Nurmikko TJ
      • Rice ASC
      • Rowbotham M
      • Serra J
      • Sommer C
      • Smith BH
      • Treede RD
      NeuPSIG guidelines on neuropathic pain assessment.
      Among the nonsurgical interventions, the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recommends pharmacology as first-line treatment.

      Connor ABO, Dworkin RH: Treatment of neuropathic pain: An overview of recent guidelines 122:S22–32, 2009.

      ,
      • Jeremy Howick
      • Chalmers Iain
      • Glasziou Paul
      • Greenhalg Trsh
      • Heneghan Carl
      • Liberti Alessandro
      • Ivan Moschetti BP
      • HT
      The 2011 Oxford CEBM Levels of Evidence (introductory Document).
      However, efficacy is limited
      • Finnerup NB
      • Sindrup SH
      • Jensen TS
      The evidence for pharmacological treatment of neuropathic pain.
      with often unacceptable side effects.
      • Finnerup NB
      • Haroutounian S
      • Baron R
      • Dworkin RH
      • Gilron I
      • Haanpaa M
      • Jensen TS
      • Kamerman PR
      • Mcnicol E
      • Moore A
      • Raja SN
      • Andersen NT
      • Sena ES
      • Smith BH
      • Rice ASC
      Neuropathic pain clinical trials: factors associated with decreases in estimated drug efficacy.
      ,
      • Finnerup NB
      • Sindrup SH
      • Jensen TS
      The evidence for pharmacological treatment of neuropathic pain.
      ,
      • Percie Du Sert N
      • Rice ASC
      Improving the translation of analgesic drugs to the clinic: Animal models of neuropathic pain.
      Over the past decade, the role of Physiotherapy and physical activity has gained increasing interest in the treatment of neuropathic pain.
      • Jesson T
      • Runge N
      • Schmid AB
      Physiotherapy for people with painful peripheral neuropathies: A narrative review of its efficacy and safety.
      Several studies have been published on the efficacy of physiotherapy on peripheral neuropathic pain resulting from systemic
      • Kanzawa-Lee GA
      • Larson JL
      • Resnicow K
      • Smith EML
      Exercise effects on chemotherapy-induced peripheral neuropathy: A comprehensive integrative review.
      or focal nerve damage.
      • Fernandez M
      • Hartvigsen J
      • Ferreira ML
      • Refshauge KM
      • Machado AF
      • Lemes ÍR
      • Maher CG
      • Ferreira PH
      Advice to stay active or structured exercise in the management of sciatica: A systematic review and meta-analysis.
      ,
      • Jesson T
      • Runge N
      • Schmid AB
      Physiotherapy for people with painful peripheral neuropathies: A narrative review of its efficacy and safety.
      In addition several guidelines propose active exercise as a treatment option for neuropathic pain.
      National Institute for Health and Care Excellence
      Low back pain and sciatica in over 16s: assessment and management (NG59).
      ,
      • Zhang YH
      • Hu HY
      • Xiong YC
      • Peng C
      • Hu L
      • Kong YZ
      • Wang YL
      • Guo JB
      • Bi S
      • Li TS
      • Ao LJ
      • Wang CH
      • Bai YL
      • Fang L
      • Ma C
      • Liao LR
      • Liu H
      • Zhu Y
      • Zhang ZJ
      • Liu CL
      • Fang GE
      • Wang XQ
      Exercise for neuropathic pain: A systematic review and expert consensus.
      Although some studies suggest that physiotherapy provides significant improvements in pain, quality of life and disability in patients with peripheral neuropathies and neuropathic pain,
      • Cleland JA
      • Childs JD
      • Palmer JA
      • Eberhart S
      Slump stretching in the management of non-radicular low back pain: A pilot clinical trial.
      ,
      • Fernández-De-Las Peñas C
      • Ortega-Santiago R
      • De La Llave-Rincón AI
      • Martínez-Perez A
      • Fahandezh-Saddi Díaz H
      • Martínez-Martín J
      • Pareja JA
      • Cuadrado-Pérez ML
      Manual physical therapy versus surgery for carpal tunnel syndrome: A randomized parallel-group trial.
      other studies did not report similar findings
      • Jesson T
      • Runge N
      • Schmid AB
      Physiotherapy for people with painful peripheral neuropathies: A narrative review of its efficacy and safety.
      and the mixed quality of studies prevents firm conclusions.
      • Jesson T
      • Runge N
      • Schmid AB
      Physiotherapy for people with painful peripheral neuropathies: A narrative review of its efficacy and safety.
      Whereas human studies evaluating physiotherapy for neuropathic pain focus on improving pain, function and quality of life, the mechanisms by which physiotherapy interventions work remains poorly understood. A better understanding of the mechanisms of action of physiotherapy would help the selection of the most promising disease modulating physiotherapy interventions for future clinical trials.
      The body of literature exploring the mechanisms of action of physiotherapeutic interventions using preclinical models has grown substantially over the past years. The main objective of this systematic review is therefore to summarize this literature by assessing the effect of physiotherapeutic interventions on biomarkers of neuropathic pain in pre-clinical models.

      Methods

      This systematic review was conducted following the guidelines of the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE), the Cochrane Handbook for Systematic Review of Intervention,
      • Higgins JPT
      GST a cargo del CCI: Manual Cochrane de revisiones sistemáticas de intervenciones.
      the original guide “Preferred Reporting Items for Systematic Reviews, PRISMA” and the most recent update from 2021.
      • Page MJ
      • McKenzie JE
      • Bossuyt PM
      • Boutron I
      • Hoffmann TC
      • Mulrow CD
      • Shamseer L
      • Tetzlaff JM MD
      Updating guidance for reporting systematic reviews: development of the PRISMA 2020 statement.
      The protocol has been prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42019142878).

      Literature Search

      A systematic search was developed following the step-by-step guide suggested by Leenaars et al.
      • Leenaars M
      • Hooijmans CR
      • van Veggel N
      • ter Riet G
      • Leeflang M
      • Hooft L
      • van der Wilt GJ
      • Tillema A
      • Ritskes-Hoitinga M
      A step-by-step guide to systematically identify all relevant animal studies.
      The following databases were searched from inception to 13th January 2020 and updated in February 2022: MEDLINE EMBASE, CINAHL, SCOPUS, Web of Science, PubMed, Cochrane library and PsycINFO. The search strategy is described in Appendix 1.

      Selection Criteria

      Types of Studies

      Original animal studies reporting the effect of physiotherapeutic interventions compared to a control group on peripheral neuropathic pain were included. Case studies, cross-over studies, and studies without a separate control group were excluded. Letters, reports, or abstracts from congresses were not included. Only articles with access to the full-text in English and Spanish language were included.

      Animal Models

      In-vivo animal models of neuropathic pain induced by both systemic (eg, diabetic or chemotherapy induced neuropathy) and focal nerve injury (eg, nerve ligation, crushing or transection) were included. We excluded studies where due to the model or validation tests (eg, sensory thresholds), we could not ascertain that the animals had developed neuropathic pain. We also excluded studies with animals with co-morbidities (eg, pre-ischemic physiologic conditions such as ischemic injury) and studies that evaluated the prevention rather than the treatment of already existing neuropathic pain.

      Interventions

      We included any physiotherapy intervention (eg, exercise, acupuncture, electro-acupuncture, joint mobilization, neural mobilization, physical agents), independent of timings and dosage. Studies evaluating invasive treatments (eg, radiofrequency or spinal stimulation) or pharmacological treatments were excluded.

      Comparator

      The control population was defined as a cohort of animals in which the same neuropathic pain model was induced, but who did either receive no treatment or a sham intervention (eg, electroacupuncture without electrical stimulation). Studies comparing physiotherapy interventions to other substantive control interventions, such as pharmacology were excluded.

      Outcome Measures

      Studies were included if they reported on the effect of the physiotherapy interventions on biomarkers related to neuropathic pain. Studies were not included if they only reported behavioral outcomes. Examples of neuropathic pain biomarkers could include:
      • 1
        Immune system: Immune cell markers (eg, CD68, CD3), markers of immune competent cells (eg, OX-42, GFAP), cytokines/chemokines
      • 2
        Neurotrohpins (eg, NGF)
      • 3
        Opioid system: Neuropeptides (eg, ࣨ-endorphine) and receptors (eg, MOR)
      • 4
        Neurotrasnmitters (eg, substance P)
      • 5
        Ion channels (eg, TRPV1, TRPV8)

      Study Selection

      Before carrying out the article selection procedure, a search for duplicates was carried out with MENDELEY. In a first phase, 2 independent reviewers (L.M and A.A.) assessed the eligibility of the studies based on information from title, abstract and keywords. During the second phase, the full text was independently reviewed by both reviewers for eligibility. A third reviewer (C.G.) acted as a mediator when there were differences of opinion between the 2 reviewers, with the 3 reviewers reaching consensus.
      • Furlan AD
      • Pennick V
      • Bombardier C
      • van Tulder M
      2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group.

      Data Extraction and Management

      Data of included studies were extracted by 2 independent reviewers (L.M and A.A.). This involved registered bibliographic data, such as first author and year of publication, animal characteristics (species, age, weight, and gender), neuropathic pain model, treatment groups and intervention characteristics (physiotherapeutic intervention, timing of intervention, number of treatment sessions, duration, dose and location). We also extracted the type of biomarkers including in which tissue they were measured. We attempted to extract means, standard deviations, and P values for all biomakers. If available, we recorded behavioral test outcomes to confirm the presence of neuropathic pain. Finally, both authors reached consensus on each item of extracted data. In case of disagreement between the authors, a third author (C.G.) made the final decision.

      Methodological Quality Assessment

      Risk of Bias Assessment

      The risk of bias of each study was assessed using SYRCLE's risk of bias tool
      • Hooijmans CR
      • Rovers MM
      • De Vries RBM
      • Leenaars M
      • Ritskes-Hoitinga M
      • Langendam MW
      SYRCLE's risk of bias tool for animal studies.
      scored by 2 independent reviewers (Y.G and E.C.). The tool provides 10 items. These categories are related to selection bias, performance bias, detection bias, attrition bias, information bias, and other biases. Half of these items match those in the tool developed by Cochrane. If there was any disagreement or discrepancy, it was resolved by a third reviewer (J.F.C.). As the tool does not include a specific cut-off, we considered studies to have low risk of bias if they were rated as high bias on less than half of the scoring criteria (<5 out of 10).

      Reporting Quality

      To evaluate the reporting quality of the studies we used the “Animals in research: reporting in vivo experiments” (ARRIVE) guidelines.
      • Kilkenny C
      • Browne WJ
      • Cuthill IC
      • Emerson M
      • Altman DG
      Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research.
      The scale has 20 items. Each item refers to a specific section of an article (eg, title, abstract), and other items refer to specific elements of preclinical research (eg, allocation of the animals, housing and husbandry). The score was assessed by 2 independent reviewers (Y.G and E.C.). Any discrepancies were resolved by consensus with a third reviewer (F.C.M). Each ARRIVE item was graduated into 3 descriptive levels: complete (green) when all sub-items in the topic have been described; partial (yellow) when one or more of the sub-items have been described; and incomplete (red) when none of the sub-items have been described. As the tool does not include a cut-off, we considered articles to have good reporting quality if they reported at least 60% of items completely.

      Qualitative Analysis

      For the description of the results, the studies were grouped by type of intervention (eg, exercise, electro-acupuncture) as well as type and location of reported biomarkers.
      Due to the heterogeneity of reported biomarkers, anatomical measurement sites and measurement methods (eg, gene expression, immunohistochemistry, protein level), and the missing summary statistics in many studies, a meta-analysis could not be carried out.
      Instead, we report these findings with heat maps for each intervention and at each location (eg, spinal cord, dorsal root ganglia): color coding was assigned according to the frequency of studies reporting any change on individual biomarker expression (eg, increase, decrease or no change) after the intervention.

      Results

      Selection of the Studies

      The database search retrieved a total of 5,038 articles. After reviewing the titles and abstracts, 179 studies were assessed for eligibility. Of those, 94 were excluded because they did not satisfy the eligibility criteria. This resulted in the inclusion of 85 full-text articles. The flow diagram is shown in Fig 1. The country that produced the most eligible studies is China (38.8%), followed by Brazil (20%) and Taiwan (16.4%). Italy, the United States and Japan contributed with 4.7% each, while Spain, South Korea and Turkey produced 3.5% of included studies. After the selection process, all articles were written in English. No articles in Spanish were found.

      Risk of Bias Analysis

      Only 2 of the 85 papers had a low risk of bias, obtaining a 5 per 10 score on the SYRCLE tool. The remaining articles had a high risk of bias (Table 1).
      Table 1Risk of Bias Assessment Using the SYRCLE Tool
      Green: low risk of bias; yellow: unclear risk of bias; red: high risk of bias.

      Reporting Quality According to ARRIVE

      Fifty-eight (71.6%) out of 85 articles were rated as 60% or more “complete” according to the ARRIVE guidelines. Twenty-one (80.8%) of the 26 articles exploring the effect of exercise are of good quality. Thirty-three percent (1 out of 3) of the acupuncture and joint mobilization articles have low quality. Of the reports on electroacupuncture, 24.14% (7 of the 29) have low methodological quality. All articles on neural mobilization showed good methodological quality (5 out of 5). Of studies including physical agents, 57.9 % (11 out of 19) were of good quality (Supplementary Table 1).

      Characteristics of the Studies

      Characteristics of the included articles, such as details of animal species, neuropathic pain models and treatment groups and interventions are shown in supplementary Table 2.
      Most studies reported on electroacupuncture (34.1%) and exercise (30.5%) followed by physical agents (23.5%), neural mobilization (6.2%), and acupuncture and joint mobilization (2.5%).
      The most widely used model of neuropathic pain was traumatic nerve injury (78.9%), with chronic constriction injury being the most studied model (55.8%) followed by sciatic nerve cut (13%). Other models reported were diabetic neuropathy, complex regional pain and chemotherapy induced neuropathy. 82.72% of the articles confirmed the presence of NeuP with behavioral tests before treatment started.
      Rats were the most prevalent species studied (85.2%) followed by mice (14.8%). Only 1 report with rabbits was included. Whereas 92.5% of studies included only male animals, 7.4 % of studies studied female animals. None of the studies included both sexes.

      Biomarkers Type and Site Examined

      The main biomarkers reported are related to the immune system (67.9%) followed by neurotrophins (27.2%), neurotransmitters (16%) and opioid pathways (7.4%. The anatomical sites where the biomarkers were measured included spinal cord (53.0% of studies), followed by the peripheral nerve and dorsal root ganglia (both 30.9%), the brain (13.6%) and blood (4.9%) (Table 2).
      Table 2Characteristics and Findings of the Included Studies in Relation to Biomarkers
      ReferenceGroupsAnatomical LevelBiomarkersMain ResultsP value
      Chang, 2013NC

      NC + acupuncture
      POD 7

      Sciatic nerve

      DRG

      Sciatic Nerve





      NF-200-stained axons (Quantification of axonal regeneration)

      % number of labelled neurons

      Quantification of Hoechst-stained nuclei

      Cdc2

      P-vim


      Increased by acupuncture

      No difference

      ?

      ?


      P < .05

      Wang, 2009CCI CCI + acupuncturePOD 15 bloodIL-1BDecrease CCI+acupunctureP < .01
      Tang, 2020Control

      Diabetic neuropathy

      Diabetic neuropathy + acupuncture
      Serum

      spinal cords

      CXCR3

      TNF-α

      IL-1β

      IL-6

      P2×4

      Decreased

      Decreased

      Decreased

      Decreased

      Decreased

      P < .001

      P < .001

      P < .001

      P < .001

      P < .001
      Cha, 2010NT NT + EAPOD ? Spinal cordNeuronal nitric oxide synthase-positive neuronsDecrease by EA in Rexed area I–II but no difference in Rexed area III–V and XP < .05
      Cha, 2012NT NT + EAPOD? Peripheral nerves

      DRG
      IL-1b

      IL-6

      TNF-Alfa

      IL-1beta

      IL-6

      TNF-Alfa
      Decrease by EA

      Decrease by EA

      Decrease by EA

      Decrease by EA

      No difference

      No difference
      P < .05

      P < .05

      P < .05

      P < .05.

      -

      -
      X.-M. Chen, 2015CCI CCI + EAPOD 14 Spinal cordP2×4R

      IFN-g
      Decrease by EA

      Decrease by EA
      P < .01

      P < .01
      Dong, 2005 (a)CCI CCI + EAPOD 14, 21 and 28 DRG















      Spinal cord
      GDNF (WB)

      GDNF (IR)

      GDNF (PCR)

      GFRα-1 (WB)

      GFRα-1 (PCR)

      GDNF (IR)
      Increase by EA at day 14 Increase by EA at days 21, and 28 Increase by EA at day 21 Increase by EA at day 28 Increase by EA at days 14 and 21 Increase by EA at day 28 Increase by EA at day 14 Increase by EA at days 21 and 28 Increase by EA at days 14 and 21 Increase by EA at day 28 Increase by EA at days 14 and 21 Increase by EA at day 28P < .05

      P < .01

      P < .05

      P < .01

      P < .01

      P < .001

      P < .05

      P < .01

      P < .05

      P < .01

      P < .01

      P < .001
      Dong, 2005 (b)CCI CCI+EAPOD 14, 21 and 28 DRG



      Spinal cord
      SOM (IR)

      SOM (PCR)

      SOM (IR)
      Increase by EA at days 14, 21 and 28 Increase by EA at days 14 and 21 Increase by EA at day 28 Increase by EA at day 14 Increase by EA at days 21 and 28P < .01

      P < .01 P < .001 P < .05

      P < .01
      Liang, 2016CCI

      CCI + EA

      CCI + sham EA
      POD After 73 hours

      Laminae I-II of ipsilateral Spinal cord dorsal horn (SCDH)


      p-p38 MAPK

      OX–42


      Decreased by EA

      Decreased by EA

      Decreased by EA


      P < .01

      P < .05

      P < .01
      Liu, 2019CCI

      CCI + EA
      POD 8

      Spinal cord







      TNF-a

      IL-1B

      IL-6

      CX3CR1


      Decreased by EA

      Decreased by EA

      Decreased by EA

      Decreased by EA


      P < .01

      P < .001

      P < .001

      P < .001
      Shao, 2015CCI EA strong manual acupuncture (smA) mild manual acupuncture (MA)POD ? Spinal cord Brain (anterior cingulate cortex)p-ERK GFAP p-ERK OX42Decrease (smA = MA)P <.01 smA = MA
      Sun, 2004CCI + PES CCI + needlingPOD 48 L5 spinal superficial laminae I-IINMDA (NR1)Decrease PES groupP < .001
      Tu, 2015CCI CCI + EAPOD 14 ipsilateral L4-6 DRGs L4-L5 lumbar spinal cords, dorsal hornNT-3

      NT-3

      IL-1β

      GFAP

      OX-42
      Increase EA

      Increase EA

      Decrease EA

      Decrease EA

      Decrease EA

      Decrease EA
      P < .001

      P < .001

      P < .001

      P = .001

      P = .003
      Tu, 2018CCI CCI + EAPOD 14 Spinal Cord L4-L6BDNF TrkBDecrease EA

      Decrease EA
      P < .001

      P < .001
      Wang, 2014CCI CCI + contralateral EA CCI + ipsilateral EAPOD 14 L4-L6 Dorsal Root Ganglia ipsilateral contralateral (P2×3)ATP ATPDecrease EA

      Decrease EA
      P < .001

      P < .001
      Wang, 2016CCI CCI + sham EA CCI + EAPOD 14 L4-L5 spinal cord (dorsal horn)IL-B

      GFAP

      TNF-a

      IL-6

      BDNF

      NGF

      NT3

      NT4
      Decrease EA

      decrease EA

      EA no difference

      decrease EA

      decrease EA

      decrease EA

      decrease EA

      decrease EA
      P < .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05
      Wang, 2018CCI

      CCI + EA
      POD 21

      Spinal Cord L4-L6
      a7nAChR IL-1BIncrease EA

      decrease EA
      P < .01

      P <.001
      Xia, 2019CCI

      CCI + EA
      POD 21 L4-L6.HMGB1

      TLR4

      CD1

      MyD88

      NF-kB
      Decrease EA

      Decrease EA

      Suppressed EA

      Suppressed EA

      Inhibited EA
      P < .01

      P < .001

      P < .01

      P < .05

      P < .05
      Xu, 2016CCI

      CCI + EA
      POD 14 L4-L5 Spinal cord ipsilateralP2×7R IL-1B, IL-18Decrease EA

      Decrease EA

      Decrease EA
      P < .0001

      P = .0026

      P = .0023
      Xue, 2015CCI

      CCI + EA
      POD ? Spinal cordBDNF

      P2×4
      Increase CCI + EA

      No significant difference
      P < .05
      Yong-Hui, 2014CCI

      CCI + 3 EA

      CCI + 5EA

      CCI + 12EA
      POD ? Blood













      Hypothalamus
      IL1-B

      IL-2

      IL-12

      IL-15

      INF-y

      IL-4-Il-10

      TGF-B beta-endorphin beta-endorphin
      Decrease 12 EA

      No significant difference

      No significant difference CCI

      No significant difference CCI

      12 EA reduce to normal

      No significant upregulated

      EA 12 EA upregulated

      All EA upregulated

      All EA upregulated
      P < .05







      P < .05



      P < .05

      P < .05

      P < .05
      Yu, 2013CCI group

      CCI + low-frequency EA

      CCI + high-frequency EA
      POD 10 Spinal CordP2 × 3 protein P2 × 3 receptorEA decrease

      EA decrease
      LEA P = .045

      HEA P = .047

      Lea versus Hea

      P < .05 to LEA
      Zhang, 2014NT

      NT + EA
      POD 7-28 Brain (arcuate nucleus)β-endorphinEA increaseP < .05
      Zhang,2018CCI

      CCI + EA
      POD 7 L4-L6 spinal cordGFAP

      IL-6

      TNF-α

      IL-1β
      CCI + EA decrease

      CCI + EA decrease

      CCI + EA decrease

      CCI + EA decrease
      P < .01

      P < .01

      P < .01

      P < .01
      Almeida, 2015CCI

      CCI + Swimming

      CCI + Swimming + Detraining
      POD 42 and 70 DRGBDNF

      GDNF

      NGF
      Decrease by swimming at day 42;

      Decrease by swimming + detraining at day 70

      No difference

      Decrease by swimming at day 42;

      No difference by swimming + detraining




      P < .05



      P < .05
      Bobinsky, 2011Non-Exer

      NC + Exercise-preoperative (Exer 1)

      NC + Exercise-preoperative-postoperative (Exer 2)

      NC + Exercise-postoperative (Exer 3)
      POD 15 Sciatic nerve





      Spinal cord
      TNF-alfa

      IL-1beta

      IL-6R

      TNF-alfa

      IL-1beta

      IL-6R

      IL-10
      Decrease by Exer 2 and Exer 3

      Decrease by Exer 1, Exer 2 and Exer 3

      No difference

      No difference

      Decrease by Exer 2 and Exer 3

      Decrease by Exer 1, Exer 2 and Exer 3

      Decrease by Exer 1, Exer 2 and Exer 3

      No difference
      P < .05

      P < .05





      P < .01

      P < .05

      P < .05
      Bobinsky, 2015NC + Sedentary

      NC + Exercise
      POD 15 Brainstem

















      Medullary raphe
      5-HT

      5-HIAA

      5-HT1A

      5-HT1B

      5-HT2A

      5-HT2C

      5-HT3A

      TNF-alfa

      IL-1beta

      SERT

      SERT
      Increase by exercise

      Increase by exercise

      No difference

      Increase by exercise

      Increase by exercise

      Increase by exercise

      No difference

      Decrease by exercise

      Decrease by exercise

      Decrease by exercise

      Decrease by exercise
      P < .001

      P < .01



      P < .05

      P < .05

      P < .05



      P < .05

      P < .05

      P < .01

      P < .05
      Bobinsky, 2018NC + Sedentary

      NC + Exercise
      POD 15 Sciatic nerve





      Spinal cord
      IL-4

      IL-1ra

      IL-5

      IL-6

      IL-4

      IL-1ra

      IL-5

      IL-6

      BDNF

      β-NGF

      GFAP Iba-1
      Increase by exercise

      Increase by exercise

      No difference

      No difference

      Increase by exercise

      Increase by exercise

      Increase by exercise

      No difference

      Decrease by exercise

      Decrease by exercise

      Decrease by exercise bilateral I-II/ipsilateral III-VI

      Decrease by exercise bilateral I-II/ipsilateral III-VI
      P < .05

      P < .05





      P < .01

      P < .01

      P < .05



      P < .01

      P < .001

      P < .05

      P < .05

      P < .01
      Y-W. Chen, 2012CC

      CCI + Swimming Exercise (CCISE)

      CCI + Treadmill Exercise (CCITE)
      POD 21 Sciatic nerveHsp72

      TNF-alfa

      IL-1beta
      Increase by CCISE

      Increase by CCITE

      ecrease by CCISE and CCITE

      Decrease by CCISE

      Decrease by CCITE
      P < .05

      P < .01

      P < .05

      P < .05

      P < .01
      Cobianchi, 2010.CCI

      CCI + EX day3-7 CCI + Ex day3-56
      POD: 7 AND 17

      Dorsal horn ipsilateral

      Ventral horn ipsilateral

      Dorsal horn contralateral

      Ventral horn contralateral
      Cd11b IR







      GFAP IR
      7 d: Decreased by exercise

      17 d: Decreased by exercise





      7 d: decreased by exercise

      17 d: No difference
      P < .01
      Cobianchi, 2013NT NT + TR

      NT + ES
      POD 1, 3, and 8 DRG





      Spinal cord
      NGF

      NT-3

      BDNF

      GDNF

      NGF

      NT-3

      BDNF





      GDNF
      Decrease by ES at day 3 but not at day 1;

      No difference at day 8

      No difference at day 1, day 3, and day 8

      Decrease by ES at day 3 but not at day 1

      Decrease by TR at day 8 No difference at day 1 and day 3;

      Decrease by TR (compared to NT and ES) at day 8

      No difference

      Increase by ES at day 1 but not at day 3;

      No difference at day 8

      No difference at day 1 and day 3

      Increase by ES at day 8 Decrease by TR (compared to NT+ES) at day 8

      Decrease by ES+TR (compared to ES) at day 8

      No difference

      Increase by ES+TR (compared to NT and TR) at day 8

      Increase by ES+TR (compared to ES) at day 8
      P < .01



      P < .05



      P < .01



      P < .05



      P < .01



      P < .01



      P < .05





      P < .001



      P < .01
      Coradini, 2015CCI

      CCI + Swim

      CCI (Obese)

      CCI + Swim (Obese)
      POD?

      Right median nerve







      GAP43



      BDNF



      Increased by CCI+swim versus CCI

      No difference between

      CI+swim (obese) and CCI (obese)

      No difference between

      CCI + swim and CCI

      No difference between

      CCI + swim (obese) and CCI (obese)


      P < .05

      Gong, 2017CCI

      CCI + exercise
      POD 31 (Postnatal day 41)

      Spinal dorsal horn Ipsilateral spinal cord


      IL-1B

      TNF-a

      CD86

      CD68

      INOS

      IL-4

      IL-10

      CD2016

      Arg

      Ym1

      CD206 + Microglia proportion

      IL-10 (western blot)

      TNF-a (western blot)


      Decreased by exercise

      Decreased by exercise

      No difference

      Decreased by exercise

      Decreased by exercise

      Increased by exercise

      Increased by exercise

      Increased by exercise

      Increased by exercise

      Increased by exercise

      Increased by exercise

      Increased by exercise

      Decreased by exercise


      P < .05

      P <. 05

      P > .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05
      Huang, 2017CCI

      CCI + TU0

      CCI + TU

      CCI + TE

      CCI + TU0 + TE

      CCI + TU + TE
      PODs 14 and 28

      Sciatic nerve









      TNF-a

      IL-6



      IL-10



      PODs 14 and 28: Decreased by TU, TE, TU0 + TE, TU + TE

      POD14: Decreased by TU, TE, TU0 + TE, TU + TE

      POD28: Decreased by TE, TU0 + TE, TU + TE

      POD14: Increased by TU, TE, TU0 + TE, TU + TE

      POD28: No difference


      P < .05



      P < .05



      P < .05



      P < .05



      P > .36
      Hung, 2014CCI CCI + TT CCI + TU CCI + TT + TUPOD 14 or 28 Spinal cordIL-6 IL-10 Iba-1Decrease by TT,TU and TT+TU at day 14 and 28 No difference at day 14; Increase by TT, TU and TT + TU at day 28

      Decrease by TT, TU and TT + TU;

      Decrease by TT + TU (compared to CCI + TT and CCI + TU)
      P < .008



      P < .01

      P < .01
      Hung, 2016CCI

      CCI + TU

      CCI + TT

      CCI + TT + TU
      PODs 14 and 28

      Spinal cords (L4 –L5)













      IL-6



      IL-10





      Iba1 IR



      PODs 14 and 28: Decreased by TT, TU, TT + TU

      POD28: Greater decrease with TT + TU compared to TT and TU

      POD14: No difference

      POD28: Increased by TT, TU and TT + TU

      POD28: Greater increase with TT + TU compared to TT and TU

      PODs 14 and 28: Decreased by TT, TU and TT+TU

      POD28: Greater decrease with TT + TU compared to TT and TU


      P < .008



      P < .05



      P > .58

      P < .01



      P < .05



      P < .01



      P < .01
      Kami, 2016aCCI-sedentary

      CCI + running
      POD 7

      Lumbar spinal cord (L4-5), superficial dorsal horns



      GABA

      GAD65/67


      Increased by running

      Increased by running


      P < .01

      P < .01
      Kami, 2016bCC_PI-sedentary

      CCI _P + running
      POD 7

      Lumbar spinal cord (L4-5), superficial dorsal horns









      .


      HDAC1 + nuclei

      HDAC1+/GFAP+ astrocytes

      HDAC1+/CD11b+ microglia

      CD11b+

      H3K9ace+/CD11b+ microglia

      CD11b+


      Decreased by running

      No difference

      Decreased by running

      No difference

      Increased by running

      No difference


      P < .01



      P < .01



      P < .01
      Korb 2010NT + trained

      NT sedentary
      POD 35-36

      SC, lumbosacral ventral horn

      SC, lumbosacral, dorsal horn, superficial laminae

      Magnus raphe nucleus

      Dorsal raphe nucleus

      Soleus muscles


      Serotonin (5-HT) immunoreactivity (lumbosacral ventral horn)

      Serotonin inmunoreactivity (superficial laminae of lumbosacral SC)

      Serotonin inmunoreactivity (magnus raphe nucleus)

      Serotonin inmunoreactivity (dorsal raphe nucleus)

      Citrate synthase enzyme activity (soleus muscle)


      Increased by training

      No difference

      No difference

      No difference

      Increases by training


      P < .05







      P < .05
      López-Álvarez, 2015.CCI + ITR1

      CCI + ITR2

      CCI
      POD 8 and 15 paw skin

      L3-L5 dorsal root ganglia
      NGF ski

      Western blot of NGF

      NGF in DRG

      GAP43 in DRG

      pNKCC1



      NKCC1

      pKCC2



      KCC2

      BDNF L3



      BDNF L5



      Iba1 l3



      Iba1 l5
      8 days: Decreased by ITR1

      15 days: Decreased by ITR1/ITR2

      8 days: Decreased by ITR1

      8 days: Decreased by ITR1

      8 days: Decreased by ITR1

      8 days: Decreased by ITR1

      15 days: Decreased by ITR1

      8 days: Decreased by ITR1

      8 days: Decreased by ITR1

      15 days: Decreased by ITR1

      15 days: Increased by ITR1

      8 days: Decreased by ITR1

      15 days: Decreased by ITR1

      8 days: Decreased by ITR1

      15 days: Decreased by ITR1/ITR2

      8 days: Decrease by ITR1

      15 days: Decreased by ITR1

      8 days: Decreased by ITR1

      15 days Decreased by iTR1

      15 days Decreased by ITR2


      P <.05

      P <.05

      P < .05

      P <.05

      P < .01

      P < .01

      P < .001

      P < .05

      P < .01

      P < .05

      P < .05

      P < .05

      P < .01

      P < .05

      P < .0001

      P < .05

      P < .05

      P < .01

      P < .05

      P < .01
      López-Álvarez, 2018.SNTR-iTR

      SNTR-sedentary
      POD 14

      Spinal Cord DH lamiae I-II.

      Brain. (periaqueductal grey matter (PAG) the locus coeruleus (LC) the dorsal raphe (DRN) the raphe magnus

      nucleus (RM)
      .

      α1A immunoreactivity





      α2A



      β2 receptor







      5HT2A
      .

      .

      ipsilateral horn: Increased by ITR

      LC and DRN: Increased by ITR



      No difference



      lamina II: increased by ITR

      the contralateral lamina I: Increased by ITR

      LC: Increased by ITR





      lamina II: Increased by ITR

      Ipsilateral lamina I: Increased by ITR

      PAG and DRN: Increased by ITR




      P < .001

      P < .05









      P < .001

      P < .01

      P < .01



      P < .01

      P < .05

      P < .01
      Martins, 2017.NC

      NC + eccentric exercise 6 m/min

      NC + eccentric exercise 10 m/min

      NC + eccentric exercise 14 m/min
      POD 63 sciatic nerve tissues

      triceps surae
      IL-1β



      TNF-α





      IL-4



      IL-1Ra



      IGF-1
      No difference



      Muscle: Decreased by Exercise

      Nerve: No difference



      No difference



      No difference



      Nerve: Increased by exercise

      Muscle: no difference




      P < .03













      P < .01
      Sumizono, 2018CCI

      CCI + high-frequency exercise

      CCI + low-frequency exercise
      POD 21 and 35

      Dorsal HORN laminae I-III







      midbrain PAG
      BDNF

      MOR

      GFAP Iba1

      B-endorphin met-enkephalin
      Decrease HFE 5 w

      Decrease all exercise 5 w

      Decrease all exercise 5 w

      Decrease all exercise 5 w

      Increase all exercise 3 w 5 w

      Increase all exercise 3 w 5 w
      P < .05

      P < .05

      P < .05

      P < .05

      P < .05

      P < .05
      Tian, 2018NT

      NT + swimming
      PODs 21, 42 and 49

      SC L4–L6









      DRG L4–L5







      Tibial nerve (neuroma)







      NGF (protein levels, ipsilateral SC)





      BDNF (protein levels, ipsilateral SC)



      NGF (protein expression, ipsilateral DRG)



      BDNF (protein expression, ipsilateral DRG)



      NGF (protein expression, ipsilateral neuroma)



      BDNF (protein expression, ipsilateral neuroma)



      Day42: Decreased by swimming

      Day49: Decrease by swimming

      Day21: No difference

      Days 42 and 49: Decreased by swimming

      Day21: No difference

      Day21: Decreased by swimming

      Days 42 and 49: No difference

      Day21: Decreased by swimming

      Days 42 and 49: No difference

      Day21: Decreased by swimming

      Days 42 and 49: No difference

      Day21: Decreased by swimming

      Days 42 and 49: No difference


      P < .01

      P < .05



      P < .01



      P < .05

      P > .05

      P < .01

      P > .05

      P < .05

      P > .05

      P < .01

      P > 0.05
      Tsai, 2017CCI

      CCI + 0%-incline treadmill

      CCI + 8%-incline treadmill
      POD 26 sciatic nerveIL-10 IL-6 TNF-aIncrease 8% treadmill

      Decrease 8% treadmill

      Decrease 8% treadmill
      P < .05

      P <.01

      P < .05
      Wang, 2016NC

      NC + Ex NC + EX + EA
      POD 31 Tibia. Substance PDecrease by exercise and exercise + EA

      Decrease exercise + EA versus exercise
      P < .05

      P < .05
      Martins, 2011NC

      NC + Anesthesia NC + AJM
      POD 35 Spinal cordGFAP

      CD11b/c
      Decrease by AJM

      Decrease by AJM (compared to anesthesia)

      Decrease by AJM

      Decrease by AJM (compared to anesthesia)
      P < .01

      P < .05

      P < .01

      P < .05
      Song, 2016CCI

      de-CCI

      de-CCI + ASMT
      POD 28 Dorsal Root Ganglia neurons L4-L5

      Blood Spinal cord L3-L6
      c-FOS

      IL-10 DRG IL-1B, IL-10, Tonfa IL-1B (DRG and SC) TNF-a (DRG and SC) IL-10 (SC)
      Decrease de-CCD + SMT

      Suppressed de-CCD + SMT

      SMT same

      SMT reduce

      SMT same

      SMT increase
      P <.01

      P <.01





      P < .05

      P < .01
      da Silva, 2015CCI

      CCI + NM
      POD 24 Sciatic nerveNGF MPZIncrease by NM

      Increase by NM
      P < .01

      P < .01
      Giardini, 2017CCI

      CCI + NM
      POD ?

      Thalamus





      Midbrain





      VPL and PAG





      GFAP

      OX-42

      BDNF

      GFAP

      OX-42

      BDNF

      GFAP

      OX42

      BDNF


      No difference

      No difference

      No difference

      No difference

      No difference

      No difference







      P > .05

      P > .05

      P > .05

      P > .05

      P > .05

      P > .05

      Santos, 2012CCI

      CCI + NM
      POD 24 Dorsal root ganglia

      Spinal cord
      NGF

      GFAP

      NGF

      GFAP
      Decrease NMP < .05
      Santos, 2018CCI

      CCI + NM
      POD 24 Dorsal root ganglia L4-L6Substance P expression of TRPV1 protein expression MOR protein expression DOR protein expression KOR b-actinDecrease NM

      Decrease NM

      Decrease NM

      Not observe immunoreactivity of these receptors not observe Immunoreactivity of these receptors

      No differences were observed
      P < .001

      P < .001

      P < .001
      Zhu, 2017diabetes diabetes + neural mobilizationPOD 31 Sciatic nerve left (no treatment)

      Sciatic nerve right (treatment)

      Dorsal root ganglion
      . IL-1B

      TNF-a

      IL-1B

      TNF-a

      IL-1B

      TNF-a
      No significant different

      MN decrease versus contralateral side

      MN decrease versus contralateral side


      P = .023

      P = .004
      Chen, 2015CC

      I CCI + TU-0

      CCI + TU-0.25

      CCI + TU-0.5

      CCI + TU-1
      POD 28 sciatic nerveTNF-a

      IL-6

      NK-1R substance P
      TU-1 decrease

      TU-1 decrease

      All TU decrease

      All TU decrease
      P < .01

      P <.05

      P < .05

      P < .05
      Cidral, 2013NC

      NC + LEDT
      POD 13 Spinal cord



      Sciatic nerve
      TNF-alfa

      IL-1beta

      IL-10

      TNF-alfa

      IL-1beta

      IL-10
      Decrease by LEDT

      No difference

      No difference

      Decrease by LEDT

      No difference

      No difference
      P < .05



      P < .05
      Cioato, 2016CCI

      CCI + sham tDCS CCI + tDCS
      POD 24 and 29 Cortex



      Spinal cord



      Brainstem
      TNF-alfa

      IL-1beta

      IL-10

      TNF-alfa

      IL-1beta

      IL-10

      TNF-alfa

      IL-1beta

      IL-10
      Increase by tDCS at day 29 but not at 24

      No difference

      No difference

      Increase by tDCS at day 29 day but not at 24

      Decrease by tDCS at days 24 and 29

      Decrease by tDCS at day 29 but not at24

      No difference

      No difference

      No difference
      P < .05



      P < .05

      P < .05

      P < .05
      Filho, 2016CCI

      CCI + Sham tDCS

      CCI + tDCS
      POD 24 or 29 Serum Spinal cord Cortex BrainstemBDNF

      BDNF

      BDNF

      BDNF
      Decrease by tDCS at day 29 but not at 24

      Increase by tDCS at day 29 but not at 24

      Decrease by tDCS at day 24 but not at 29

      Decrease by tDCS at days 24 and 29
      P < .05

      P < .05

      P < .05

      P < .05
      Giuliani, 2004CCI

      CCI + laser
      POD?

      Laminae I and II of the dorsal horn of spinal cord (L3-L5)


      Enkephalin mRNA


      No difference
      .
      Hsieh, 2012CCI + laser

      CCI + sham
      POD 14

      Sciatic nerve



















      H&E study (nuclei percentage)

      ED1 immunoreactivity

      TNF-a

      IL-1B

      Cytokine

      HIF-1a-positive cells (inmunoreactivity)

      HIF-1a (protein levels, immunoblotting)

      VEGF positive cells (inmunoreactivity)

      NGF positive cells (inmunoreactivity)

      S100 positive cells (inmunoreactivity)

      VEGF (protein levels, immunoblotting)

      NGF (protein levels, immunoblotting)


      Decreased by laser

      Decreased by laser

      Decreased by laser

      Decreased by laser

      Decreased by laser

      Decreased by laser

      Decreased by laser

      Increased by laser

      Increased by laser

      Increased by laser

      Increased by laser

      Increased by laser


      P < .05

      P < .05

      P < .05

      P < .05

      P <.0001

      P = .006

      P = .006

      P = .009

      P = .002

      P = .005

      P = .009

      P = .002
      Hsieh, 2017Oxaliplatin + TUS

      Oxaliplatin + shamTUS
      POD 24

      L2–L6 DRG.

      .

      Superficial laminae (dorsal horn) in lumbar spinal cord (at segments L2–L6)


      TRPM8

      TRPV1



      SP-like immunoreactivity


      Decreased by TUS

      No difference



      Decreased by TUS


      P < .05

      P > .05



      P < .05
      Lin, 2015CCI

      CCI + HFS
      POD 7

      affected sciatic nerve


      TNF-a
      No difference
      Liu, 2017CCI + sham PEMF

      CCI + PEMF
      POD 14

      Sciatic nerve Dorsal root ganglion Spinal cord


      HCN1 mRNA

      HCN2 mRNA
      No difference

      No difference
      Matsuo, 2014.CCI

      CCI + TENS 1 w CCI + TENS 2 w
      POD 8 spinal cord dorsal hornIba1 immunoreactivity

      BrdU-positive/Iba1-positive

      GFAP immunoreactivity

      p-p38 in microglia

      PKC-y

      p-CREB

      MAP kinases (p-p38, p-ERK1/2, p-JNK)

      proinflammatory cytokines (IL-1, TNF-, IL-6)

      opioid receptors (μOR and OR)
      Decreased by TENS

      Decreased by TENS

      Decreased by TENS

      Decreased by TENS

      Decreased by TENS

      Decreased by TENS

      Decreased by TENS

      Decreased by TENS

      Dncreased by TENS
      P < .05
      Mert, 2015asham PMF (SPMF)

      PMF-AD

      PMF-AW
      POD 28-35 sciatic nerve tissuesIL-1 beta

      IL-6

      IL-10
      Decreased by PMF

      Decreased by PMF

      increased by PMF



      PMF-AD > PMF-AW
      P < .05
      Mert, 2017CCI + PMF

      CCI + SPMF
      POD: 35

      sciatic nerve tissues
      IL-1b

      IL-6

      IL-10
      Decreased by PMF

      Decreased by PMF

      Increase by PMF
      P < .05

      P < .05

      P < .05
      Somers, 2003CCI

      CCI + TENS
      POD 12 Spinal cordAspartate

      Glutamate

      Glycine

      GABBA
      Decrease by TENS

      Decrease by TENS

      Decrease by TENS

      No difference
      P < .05

      P < .05

      P < .05
      Somers, 2009CCI

      CCI + high frequency TENS contralateral

      CCI + low-frequency TENS

      CCI + randomly TENS
      POD ? Dorsal HornAspartate

      Glutamate

      Glycine

      GABA
      Increase randomly

      TENS Increase randomly

      TENS Increase randomly

      TENS Increase high frequency TENS
      P < .001

      P < .001

      P < .001

      P < .014
      Su, 2018NC

      NC + High-frequency immediately(HFI)

      NC + High-frequency 7 days after(HFL)

      NC + Low-frequency immediately (LFI)

      NC + Low-frequency 7 days after (HFL)
      POD:4 wk after treatments

      The distal end of the nerve



      Dorsal root ganglion



      Somatosensory cortex and hippocampus



      S-100

      Neurofilament (NF)

      TNF-a

      Synaptophysin

      TNF-a

      Synaptophysin


      Increased by HFI and HFL versus NC and LFI

      Increased by HFI and HFL versus NC and LFI

      Increased by HFI versus NC and HFL

      Increased by HFI versus NC and HFL

      Increased by HFI versus NC and HFL

      Increased by HFI versus NC and HFL


      P < .01

      P < .01

      P < .01

      P < .01

      P < .01

      P < .01
      Yang, 2018CCI + sham-rTMS group CCI + 1 Hz group CCI + 20 Hz groupPOD 13 L4-L6 Dorsal Root Ganglia ipsilateral Dorsal horn I-IVnNOs/B-actin

      GFAP
      CCI + 20 HZ decrease 20 HZ

      CCI + 20 Hz decrease
      P < .01

      P < .05
      Yueh-Ling, 2012CCI and treated with laser CCI and treated with sham irradiationPOD sciatic nerveIL-1B

      TNF-a

      HIF-1a

      VEGF

      NFG
      Decrease after laser

      Decrease after laser

      Decreased after laser

      Increase in laser

      Increase in laser
      P < .0001

      P < .0001

      P = .006

      P = .009

      P = .002
      Wang, 2020Sham

      Injury + EA

      Injury

      Spinal cordIRF8

      CD11b

      CX3CRl
      Decreased

      Decreased

      Decreased
      P < .001

      P < .001

      P < .001
      Li, 2019CIPN

      CIPN + EA

      CIPN + sham EA
      POD 14

      L4–6 DRGs









      Spinal cord dorsal horn (SCDH)







      TRPV1 (normalized fluorescence intensity [%])

      TRPV1 (% of TRPV1 + Neuron [among neuron+])

      TRPV1 (Western blotting)

      TLR4

      MyD88

      GFAP (staining intensity)

      GFAP (number of positive cells)

      OX42 (staining intensity)

      OX42 (number of positive cells)


      Decreased by EA versus sham EA

      Decreased by EA versus sham EA

      Decreased by EA versus sham EA

      Decreased by EA versus sham EA

      Decreased by EA versus sham EA

      Decreased by EA versus sham EA

      Decreased by EA versus sham EA

      Decreased by EA versus sham EA

      Decreased by EA versus sham EA


      P <.01

      P <.01

      P <.01

      P <.01

      P <.01

      P <.01

      P <.01

      P <.01

      P <.01
      Hsieh, 2017Oxaliplatin + TUS

      Oxaliplatin + shamTUS
      POD 24

      L2–L6 DRG.

      .

      Superficial laminae (dorsal horn) in lumbar spinal cord (at segments L2–L6)


      TRPM8

      TRPV1



      SP-like immunoreactivity


      Decreased by TUS

      No difference



      Decreased by TUS


      P < .05

      P > .05



      P < .05
      Zhao, 2020Control group

      PTX group

      PTX +

      EA group

      PTX + sham EA group
      Spinal cord

      Serum
      GFAP

      TLR4

      NF-κ B

      IL-1β

      TNF-α

      Decreased

      ​​ Decreased

      Decreased

      ​​

      Decreased

      Decreased

      P < .05

      P < .01

      P < .01

      P < .01

      P < .01
      Belmonte, 2018CPIP CPIP + Exercise continous CPIP + Exercise interval protocolPOD 11 Spinal cordTNF-alfa IL-1beta IL-6 IL-10 ERK1/2 AKT1/2/3Decrease by exercise continuous protocol and exercise interval protocol

      No difference

      Decrease by exercise continuous protocol and exercise interval protocol

      Increase by exercise continuous protocol and exercise interval protocol

      Increase by exercise continuous protocol; decrease by exercise interval protocol

      No difference
      P < .05



      P < .05

      P < .05

      P < .05
      Manni, 2011.12 STZ group

      12 STZ group + EA
      POD 28 skin

      DRG
      NGF skin

      NGF Spinal Cord

      substance P (SP) skin

      substance P (SP) spinal cord

      NGF receptor TrkA skin

      pTyr496-TrkA

      transient receptor potential vanilloid 1 (TRPV1) skin

      spinal TrkA

      pTyr496-TrkA in the spinal cord

      TRPV1 in spinal cord

      GABA–GAD-67
      No difference

      Decreased by EA

      Decreased by EA

      Decreased by EA

      Decreased by EA

      Decreased by EA

      Increased by EA

      Decreased by EA

      Decreased by EA

      Decreased by EA

      Increased by EA


      P < .05
      Nori, 2013.DN

      DN + EA
      POD:28

      DRG
      NGF Protein.

      NGF mRNA production.

      NGF Receptor:

      TrkA mRNA

      TrkA protein

      pTyr496-TrkA

      mRNA-p75NTR

      p75NTR protein

      ERK1-2

      Akt

      JNKp38

      phospho-IκB-α

      phosphorylation of the IκB-α

      TRPV-1

      phosphorylated p38
      Decreased by EA

      No difference



      Decreased by EA

      No difference

      Decreased by EA

      No difference

      Decreased by EA

      No difference

      No difference

      Increased by EA

      Increased by EA

      Increased by EA

      Decreased by EA

      No difference
      P < .05
      Shi, 2013Diabetes diabetes + EAPOD 30

      Dorsal root ganglia L4-L5
      . CBS (cystathionine b synthase) p65 b-actin NF-kBDecrease EA

      Decrease EA



      Decrease EA

      No difference
      . P < .05.

      P < .05.

      P < .05.
      Y-W. Chen, 2013Sedentary + DN

      Exercise + DN
      POD 14,

      28 or 56 Spinal cord



      Peripheral nerves
      Hsp72

      TNF-alfa

      IL-6

      Hsp72

      TNF-alfa

      IL-6
      Increase by exercise

      No difference

      No difference

      Increase by exercise

      No difference

      No difference
      P < .05



      P < .05
      Y-W. Chen, 2015Sedentary + DN

      Exercise + DN
      POD 14 and 28 Sciatic nerveIL-10

      IL-6

      TNF-α

      MDA
      Increase by exercise at days 14 and 28

      Decrease by exercise at days 14 and 28

      Decrease by exercise at days 14 and 28

      Decrease by exercise at day 14 but not 28
      P < .0051

      P < .01

      P < .01

      P < .01
      Ma, 2018.DN

      DN + EX
      POD 35 DRGIL-1b

      IL-6

      TNF-a

      IL1R

      IL6R

      TNFR1
      Decreased by exercise

      Decreased by exercise

      Decreased by exercise

      Decreased by exercise

      Decreased by exercise

      Decreased by exercise
      P < .05
      Thakur, 20161diabetes

      2diabetic + exercise
      POD 42 Spinal cord dorsal hornIL-1B macrophage (CD11b,CD6) CGRPDecrease exercise Decrease exercise Preservation exerciseP < .05

      P < .001
      Mert, 2015bSTZ-induced diabetic L-PMF-treated diabetic H-PMF-treated diabeticPOD: 35

      Spinal cord sciatic nerve tissues
      TNF-alpha









      IL-1 beta









      IL-6











      IL-10
      Spinal cord: decreased L-PMF

      decreased by H-PMF

      Sciatic nerve: decreased by L-PMF

      No difference by H-PMF



      Spinal cord: decreased by L-PMF

      increased by H-PMF

      Sciatic nerve: decreased by L-PMF

      decreased by H-PMF



      Spinal cord: decreased by L-PMF

      No difference by H-PMF

      Sciatic nerve: No difference by L-PMF

      Increased by H-PMF

      Spinal cord: increased by L-PMF

      No difference by H-PMF

      Sciatic never: No difference by L-PMF

      decreased by H-PMF
      P < .05
      da Silva Oliveira, 2018DN + Sham

      DN + PBM
      POD 35 Sciatic nerveNGFIncrease by PBMP = .0133
      Tang, 2020Control

      Diabetic neuropathy

      Diabetic neuropathy + acupuncture
      Serum

      spinal cords

      CXCR3

      TNF-α

      IL-1β

      IL-6

      P2×4

      Decreased

      ​​ Decreased

      Decreased

      Decreased

      Decreased

      P < .001

      P < .001

      P < .001

      P < .001

      P < .001


      Wang, 2021
      Control

      Model

      EA
      Sciatic nerve

      IL 1b

      IL 6

      TNF-a
      Decreased

      Decreased

      Decreased
      P < .01

      P < .01

      P < .05

      Abbreviations: NC, nerve crush; CCI, chronic constriction injury; NT, nerve transection; CPIP, chronic post-ischemia pain; STZ, streptozocin; DN, diabetic neuropathy; SNTR, sciatic nerve transection and repair; POD, post operative day; ?, not reported; ES, electrical stimulation; PES, percutaneus electrical stimulation; HFE, high frequency exercise; PMF, pulse magnetic field; SPMF, sham pulse magnetic field; EX, exercise; EA, electro-acupuncture; AJM, ankle joint mobilization; SMT, spinal manipulative therapy; HFI, high-frequency immediately; HFL, low-frecuency immediately; tDCS, trasncraneal direct current stimulation; DRG, dorsal root ganglia; PAG, periaqueductal grey; SC, spinal cord; SCDH, spinal cord dorsal horn; WB, western blot; PCR, polymerase chain reaction; IL, interleukin; TNF, tumor necrosis factor; TGF, transformin growth factor; MyD-88, myeloid differentiation primary response 88; NGF, nerve growth factor; NT-3, neurotrophin 3; BDNF, brain derived neurotrophic factor; GDNF, glial cell derived neurotrophic factor; GAP-43, growth asociated protein 43; VEGF, vascular endothelial growth factor; GFAP, glial fribillary acidic protein; MDA, mor M-opioid receptor, dor D-opioid receptor, kor k-opioid receptor; TRPV1, transient receptor potential cation channel subfamily V member 1; NMDA, N-nitrosodimethylamine; TRPV8, transient receptor potential cation channel subfamily V member 8; ATP, adenosine triphosphate; OX-42, IFN-y, interferón gamma; NF-kb, nuclear factor-kb; CX3CR1. chemoline receptor 1, cd11b; CD68, cluster of differentiation 68; CD86, cluster of differentiation 86.

      Qualitative Analysis

      Supplementary Table 1 contain heat maps reflecting the frequency of studies showing specific directions of effects (up vs downregulation vs no change) of each physiotherapy intervention on biomarkers of neuropathic pain.

      Exercise

      Two types of exercises were investigated in the studies, swimming, and treadmill running.
      Swimming was one of the two activities studied by 4 out of 26 studies (15.4%). The dose for swimming exercise ranged from 40 to 60 minutes and was performed on 5 days per week. Swimming reduced the concentration of proinflammatory cytokines in the injured nerve tissue,
      • Chen Y-W
      • Li Y-T
      • Chen YC
      • Li Z-Y
      • Hung C-H
      Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve.
      as well as the concentration of neurotrophins in spinal cord, dorsal root ganglia, and peripheral nerve tissue in the medium term.
      • Almeida C
      • DeMaman A
      • Kusuda R
      • Cadetti F
      • Ravanelli MI
      • Queiroz AL
      • Sousa TA
      • Zanon S
      • Silveira LR
      • Lucas G
      Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain.
      ,
      • TIAN J
      • YU T
      • XU Y
      • PU S
      • LV Y
      • ZHANG XIN
      • DU D
      Swimming training reduces neuroma pain by regulating neurotrophins.
      Only 1 article found no post-treatment differences in BDFN concentrations.
      • Coradini JG
      • Kunz RI
      • Kakihata CMM
      • Errero TK
      • Bonfleur ML
      • de Fátima Chasko Ribeiro L
      • Brancalhão RMC
      • Bertolini GRF
      Swimming does not alter nociception threshold in obese rats submitted to median nerve compression.
      One paper found an increase of GAP-43 in the peripheral nerve.
      • Coradini JG
      • Kunz RI
      • Kakihata CMM
      • Errero TK
      • Bonfleur ML
      • de Fátima Chasko Ribeiro L
      • Brancalhão RMC
      • Bertolini GRF
      Swimming does not alter nociception threshold in obese rats submitted to median nerve compression.
      Treadmill aerobic training was the most used by the studies (23 out of 26 studies, 88.5%), both in isolation and using it against other therapies. The dose of treadmill running ranged from 60 minutes to exhaustion and was performed between 3 and 5 days per week over a period of 3 to 8 weeks. Treadmill running was able to reduce proinflammatory cytokines and increase anti-inflammatory cytokines mainly in peripheral nerves,
      • Chen Y-W
      • Chiu C-C
      • Hsieh P-L
      • Hung C-H
      • Wang J-J
      Treadmill training combined with insulin suppresses diabetic nerve pain and cytokines in rat sciatic nerve.
      ,
      • Chen Y-W
      • Hsieh P-L
      • Chen Y-C
      • Hung C-H
      • Cheng J-T
      Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats.
      ,
      • Huang PC
      • Tsai KL
      • Chen YW
      • Lin HT
      • Hung CH
      Exercise combined with ultrasound attenuates neuropathic pain in rats associated with downregulation of IL-6 and TNF-α, but with upregulation of IL-10.
      ,
      • Tsai K-L
      • Huang P-C
      • Wang L-K
      • Hung C-H
      • Chen Y-W
      Incline treadmill exercise suppresses pain hypersensitivity associated with the modulation of pro-inflammatory cytokines and anti-inflammatory cytokine in rats with peripheral nerve injury.
      with changes in DRG and spinal cord also reported.
      • Belmonte LAO
      • Martins TC
      • Salm DC
      • Emer AA
      • de Oliveira BH
      • Mathias K
      • Goldim MP
      • Horewicz VV
      • Piovezan AP
      • Bobinski F
      • Petronilho F
      • Martins DF
      Effects of different parameters of continuous training and high-intensity interval training in the chronic phase of a mouse model of complex regional pain syndrome type I.
      ,
      • Bobinski F
      • Ferreira TAA
      • Córdova MM
      • Dombrowski PA
      • da Cunha C
      • Santo CC
      • Poli A
      • Pires RGW
      • Martins-Silva C
      • Sluka KA
      • Santos ARS
      Role of brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic pain after sciatic nerve injury in mice.
      • Bobinski F
      • Martins DF
      • Bratti T
      • Mazzardo-Martins L
      • Winkelmann-Duarte EC
      • Guglielmo LGA
      • Santos ARS
      Neuroprotective and neuroregenerative effects of low-intensity aerobic exercise on sciatic nerve crush injury in mice.
      • Bobinski F
      • Teixeira JM
      • Sluka KA
      • Santos ARS
      Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain.
      ,
      • Chen Y-W
      • Hsieh P-L
      • Chen Y-C
      • Hung C-H
      • Cheng J-T
      Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats.
      ,
      • Gong X
      • Chen Y
      • Fu B
      • Jiang J
      • Zhang M
      Infant nerve injury induces delayed microglial polarization to the M1 phenotype, and exercise reduces delayed neuropathic pain by modulating microglial activity.
      ,
      • Thakur V
      • Gonzalez M
      • Pennington K
      • Nargis S
      • Chattopadhyay M
      Effect of exercise on neurogenic inflammation in spinal cord of Type 1 diabetic rats.
      Only one article found increased proinflammatory cytokines in nerve and dorsal horn of the spinal cord.
      • Bobinski F
      • Teixeira JM
      • Sluka KA
      • Santos ARS
      Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain.
      Only 1 study found no difference in the sub-group “other inflammatory markers” of the immune system
      • Kami K
      • Taguchi S
      • Tajima F
      • Senba E
      Histone acetylation in microglia contributes to exercise-induced hypoalgesia in neuropathic pain model mice.
      The concentration of neurotrophins was lowered after treadmill exercise.
      • Cobianchi S
      • Casals-Diaz L
      • Jaramillo J
      • Navarro X
      Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury.
      ,
      • Lopez-Alvarez VM
      • Modol L
      • Navarro X
      • Cobianchi S
      Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury.
      ,
      • Sumizono M
      • Sakakima H
      • Otsuka S
      • Terashi T
      • Nakanishi K
      • Ueda K
      • Takada S
      • Kikuchi K
      The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model.
      ,
      • TIAN J
      • YU T
      • XU Y
      • PU S
      • LV Y
      • ZHANG XIN
      • DU D
      Swimming training reduces neuroma pain by regulating neurotrophins.
      One study reported increased expression of at least one of these biomarkers when treadmill running was combined with electrical stimulation.
      • Cobianchi S
      • Casals-Diaz L
      • Jaramillo J
      • Navarro X
      Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury.
      Treadmill running was also effective in reducing the activation of glial cells in DRG and spinal cord.
      • Bobinski F
      • Teixeira JM
      • Sluka KA
      • Santos ARS
      Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain.
      ,
      • Ching-Hsia H
      • Po-Ching H
      • Jann-Inn T
      • Jhi-Joung W
      • Yu-Wen C
      Therapeutic ultrasound and treadmill training suppress peripheral nerve injury-induced pain in rats.
      ,
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
      ,
      • Kami K
      • Taguchi S
      • Tajima F
      • Senba E
      Histone acetylation in microglia contributes to exercise-induced hypoalgesia in neuropathic pain model mice.
      ,
      • Lopez-Alvarez VM
      • Modol L
      • Navarro X
      • Cobianchi S
      Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury.
      Only 1 article did not find changes in the spinal cord after intervention.
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
      In that experiment, the animals ran until exhaustion,
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
      while in the others it was of a fixed duration.
      • Bobinski F
      • Teixeira JM
      • Sluka KA
      • Santos ARS
      Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain.
      ,
      • Ching-Hsia H
      • Po-Ching H
      • Jann-Inn T
      • Jhi-Joung W
      • Yu-Wen C
      Therapeutic ultrasound and treadmill training suppress peripheral nerve injury-induced pain in rats.
      ,
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
      ,
      • Kami K
      • Taguchi S
      • Tajima F
      • Senba E
      Histone acetylation in microglia contributes to exercise-induced hypoalgesia in neuropathic pain model mice.
      ,
      • Lopez-Alvarez VM
      • Modol L
      • Navarro X
      • Cobianchi S
      Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury.
      Studies reported a direct relationship between increased expression of inhibitory neurotransmitters, such as serotonin in the brain and spinal cord and exposure to treadmill running.
      • Korb A
      • Bonetti L V
      • Da Silva SA
      • Marcuzzo S
      • Ilha J
      • Bertagnolli M
      • Partata WA
      • Faccioni-Heuser MC
      Effect of treadmill exercise on serotonin immunoreactivity in medullary raphe nuclei and spinal cord following sciatic nerve transection in rats.
      ,
      • Lopez-Alvarez VM
      • Puigdomenech M
      • Navarro X
      • Cobianchi S
      Monoaminergic descending pathways contribute to modulation of neuropathic pain by increasing-intensity treadmill exercise after peripheral nerve injury.
      ,
      • Sumizono M
      • Sakakima H
      • Otsuka S
      • Terashi T
      • Nakanishi K
      • Ueda K
      • Takada S
      • Kikuchi K
      The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model.
      Only 1 study found a decrease in neurotrophin expression in the peripheral nerve.
      • Chen Y-W
      • Chiu C-C
      • Hsieh P-L
      • Hung C-H
      • Wang J-J
      Treadmill training combined with insulin suppresses diabetic nerve pain and cytokines in rat sciatic nerve.
      In contrast, the effect on excitatory neurotransmitters was only evaluated in 2 articles, with mixed results, however different neurotransmitters were measured (GABA and Substance P).
      • Kami K
      • Tajima F
      • Senba E
      Activation of cyclic AMP response element-binging protein in dopaminergic neurons in the ventral tegmental area via voluntary wheel running contributes to exercise-induced hypoalgesia in a mouse model of neuropathic pain.
      ,
      • Wang Y
      • Tang Q
      • Zhu L
      • Huang R
      • Huang L
      • Koleini M
      • Zou D
      Effects of treatment of treadmill combined with electro-acupuncture on tibia bone mass and substance PExpression of rabbits with sciatic nerve injury.
      Two articles reported a decline in the expression of inflammatory markers in the dorsal horn.
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
      ,
      • Thakur V
      • Gonzalez M
      • Pennington K
      • Nargis S
      • Chattopadhyay M
      Effect of exercise on neurogenic inflammation in spinal cord of Type 1 diabetic rats.

      Neural Mobilization

      Five articles studied neural mobilization. The most frequently reported dose was 20 oscillations per minute for 2 minutes and 25 seconds of rest, for 10 minutes for a total of 10 sessions. Only 1 showed no difference in posttreatment biomarkers of neuropathic pain.
      • Giardini AC
      • Santos FM
      • Dos Da
      • Silva JT
      • De Oliveira ME
      • Martins DO
      • Chacur M
      Neural mobilization treatment decreases glial cells and brain-derived neurotrophic factor expression in the central nervous system in rats with neuropathic pain induced by CCI in rats.
      Whereas Giardini et al
      • Giardini AC
      • Santos FM
      • Dos Da
      • Silva JT
      • De Oliveira ME
      • Martins DO
      • Chacur M
      Neural mobilization treatment decreases glial cells and brain-derived neurotrophic factor expression in the central nervous system in rats with neuropathic pain induced by CCI in rats.
      evaluated changes in the thalamus, midbrain and PAG, the other studies examined biomarkers in SCDH, DRG, and sciatic nerve. Neural mobilization consistently reduced the concentration of neurotrophic factors and the expression of substance P, TRPV1, and MOR
      • Santos FM
      • Silva JT
      • Giardini AC
      • Rocha PA
      • Achermann AP
      • Alves AS
      • Britto LR
      • Chacur M
      Neural mobilization reverses behavioral and cellular changes that characterize neuropathic pain in rats.
      ,
      • Santos FM
      • Silva JT
      • Rocha IRC
      • Martins DO
      • Chacur M
      Non-pharmacological treatment affects neuropeptide expression in neuropathic pain model.
      in the spinal cord. One article reported an increased concentration of NGF in the sciatic nerve.
      • da Silva JT
      • Santos FM dos
      • Giardini AC
      • Martins D de O
      • de Oliveira ME
      • Ciena AP
      • Gutierrez VP
      • Watanabe IS
      • Britto LRG de
      • Chacur M
      Neural mobilization promotes nerve regeneration by nerve growth factor and myelin protein zero increased after sciatic nerve injury.
      Whereas most studies used the chronic constriction model, one used a diabetic neuropathy model
      • Zhu GC
      • Tsai KL
      • Chen YW
      • Hung CH
      Neural mobilization attenuates mechanical allodynia and decreases proinflammatory cytokine concentrations in rats with painful diabetic neuropathy.
      and reported a decrease in intraneural proinflammatory cytokines on the treated side.

      Joint Mobilization

      Two studies evaluated the effect of joint mobilization on biomarkers of neuropathic pain. The dose for joint mobilization ranged from 1 series of 10 repetitions to 3 minutes series with 30 seconds’ rest. The frequency ranged from every 2 days to 5 consecutive days for a total of 12 to 15 days. Joint mobilization consistently reduced activation of the immune system (glial cells mainly) in the SCDH.
      • Martins DF
      • Mazzardo-Martins L
      • Gadotti VM
      • Nascimento FP
      • Lima DAN
      • Speckhann B
      • Favretto GA
      • Bobinski F
      • Cargnin-Ferreira E
      • Bressan E
      • Dutra RC
      • Calixto JB
      • Santos ARS
      Ankle joint mobilization reduces axonotmesis-induced neuropathic pain and glial activation in the spinal cord and enhances nerve regeneration in rats.
      Their effect on cytokine expression revealed controversial results; while the concentration of cytokines in the DRG remained the same after treatment, only anti-inflammatory cytokines increased their expression in the spinal cord.
      • Song XJ
      • Huang ZJ
      • Song WB
      • Song XS
      • Fuhr AF
      • Rosner AL
      • Ndtan H
      • Rupert RL
      Attenuation effect of spinal manipulation on neuropathic and postoperative pain through activating endogenous anti-inflammatory cytokine interleukin 10 in rat spinal cord.
      One of the 2 studies used rhythmic mobilization techniques
      • Martins DF
      • Mazzardo-Martins L
      • Gadotti VM
      • Nascimento FP
      • Lima DAN
      • Speckhann B
      • Favretto GA
      • Bobinski F
      • Cargnin-Ferreira E
      • Bressan E
      • Dutra RC
      • Calixto JB
      • Santos ARS
      Ankle joint mobilization reduces axonotmesis-induced neuropathic pain and glial activation in the spinal cord and enhances nerve regeneration in rats.
      and the other high-speed manipulations.
      • Song XJ
      • Huang ZJ
      • Song WB
      • Song XS
      • Fuhr AF
      • Rosner AL
      • Ndtan H
      • Rupert RL
      Attenuation effect of spinal manipulation on neuropathic and postoperative pain through activating endogenous anti-inflammatory cytokine interleukin 10 in rat spinal cord.
      The place of application was different as well as the dose, so the results must be interpreted with caution.

      Physical Agents

      Nineteen studies investigated a range of physical agents including laser, therapeutic ultrasound, and transcranial direct current stimulation. The dose for ultrasound most frequently reported was 1 MHz 0.5 to 1 w/cm2 during 5 minutes.
      Therapeutic ultrasound reduced the expression of substance P in both studies.
      • Chen YW
      • Tzeng JI
      • Huang PC
      • Hung CH
      • Shao DZ
      • Wang JJ
      Therapeutic ultrasound suppresses neuropathic pain and upregulation of substance p and neurokinin-1 receptor in rats after peripheral nerve injury.
      ,
      • Hsieh YL
      • Chen HY
      • Yang CH
      • Yang CC
      Analgesic effects of transcutaneous ultrasound nerve stimulation in a rat model of oxaliplatin-induced mechanical hyperalgesia and cold allodynia.
      Further, a reduction of cytokines (tumor necrosis factor [TNF] and interleukin-6 [IL-6])
      • Chen YW
      • Tzeng JI
      • Huang PC
      • Hung CH
      • Shao DZ
      • Wang JJ
      Therapeutic ultrasound suppresses neuropathic pain and upregulation of substance p and neurokinin-1 receptor in rats after peripheral nerve injury.
      and TRPV1 expression
      • Hsieh YL
      • Chen HY
      • Yang CH
      • Yang CC
      Analgesic effects of transcutaneous ultrasound nerve stimulation in a rat model of oxaliplatin-induced mechanical hyperalgesia and cold allodynia.
      was apparent at sciatic nerve and dorsal root ganglia respectively.
      Of the 5 articles including laser therapy, only 1 measured the changes generated on enkephalines
      • Giuliani A
      • Fernandez M
      • Farinelli M
      • Baratto L
      • Capra R
      • Rovetta G
      • Monteforte P
      • Giardino L
      • Calzà L
      Very low level laser therapy attenuates edema and pain in experimental models.
      with no changes after treatment. Three papers report a decrease of cytokine concentration.
      • Cidral-Filho FJ
      • Martins DF
      • More AOO
      • Mazzardo-Martins L
      • Silva MD
      • Cargnin-Ferreira E
      • Santos ARS
      Light-emitting diode therapy induces analgesia and decreases spinal cord and sciatic nerve tumour necrosis factor-alpha levels after sciatic nerve crush in mice.
      ,
      • Hsieh Y-L
      • Chou L-W
      • Chang P-L
      • Yang C-C
      • Kao M-J
      • Hong C-Z
      Low-level laser therapy alleviates neuropathic pain and promotes function recovery in rats with chronic constriction injury: possible involvements in hypoxia-inducible factor 1alpha (HIF-1alpha).
      All laser treatments increased the concentration of NGF in the sciatic nerve regardless of the time of intervention or parameters applied.
      • da Silva OR
      • Cury DP
      • Yamashita LB
      • Esteca M v
      • Watanabe I-S
      • Bergmann YF
      • Toniolo EF
      • Dale CS
      Photobiomodulation induces antinociception, recovers structural aspects and regulates mitochondrial homeostasis in peripheral nerve of diabetic mice.
      ,
      • Hsieh Y-L
      • Chou L-W
      • Chang P-L
      • Yang C-C
      • Kao M-J
      • Hong C-Z
      Low-level laser therapy alleviates neuropathic pain and promotes function recovery in rats with chronic constriction injury: possible involvements in hypoxia-inducible factor 1alpha (HIF-1alpha).
      Cidral et al
      • Cidral-Filho FJ
      • Martins DF
      • More AOO
      • Mazzardo-Martins L
      • Silva MD
      • Cargnin-Ferreira E
      • Santos ARS
      Light-emitting diode therapy induces analgesia and decreases spinal cord and sciatic nerve tumour necrosis factor-alpha levels after sciatic nerve crush in mice.
      found a decrease in the concentration of TNF but not IL-1β in the SC and the sciatic nerve while Hsieh et al
      • Held M
      • Karl F
      • Vlckova E
      • Rajdova A
      • Escolano-Lozano F
      • Stetter C
      • Bharti R
      • Förstner KU
      • Leinders M
      • Dušek L
      • Birklein F
      • Bednarik J
      • Sommer C
      • Üçeyler N
      Sensory profiles and immune-related expression patterns of patients with and without neuropathic pain after peripheral nerve lesion.
      reported a decrease of several cytokines measured in the sciatic nerve. This difference could be due to the different intensities applied in the studies. Cidral et al
      • Ching-Hsia H
      • Po-Ching H
      • Jann-Inn T
      • Jhi-Joung W
      • Yu-Wen C
      Therapeutic ultrasound and treadmill training suppress peripheral nerve injury-induced pain in rats.
      used 80 mW/cm2 and 2.5 J/cm2 versus 30 mW/cm2 and 9 J/cm2 used by Hsieh et al
      • Hsieh Y-L
      • Chou L-W
      • Chang P-L
      • Yang C-C
      • Kao M-J
      • Hong C-Z
      Low-level laser therapy alleviates neuropathic pain and promotes function recovery in rats with chronic constriction injury: possible involvements in hypoxia-inducible factor 1alpha (HIF-1alpha).
      in both studies.
      Two studies investigated tDCS. tDCS increased TNF-a concentrations in the brain and spinal cord, whereas IL-1b and IL-10 only changed significantly in the spinal cord, with a decreasing concentration of both cytokines.
      • Cioato SG
      • Medeiros LF
      • Marques Filho PR
      • Vercelino R
      • De Souza A
      • Scarabelot VL
      • De Oliveira C
      • Adachi LNS
      • Fregni F
      • Caumo W
      • Torres ILS
      Long-lasting effect of transcranial direct current stimulation in the reversal of hyperalgesia and cytokine alterations induced by the neuropathic pain model.
      tDCS also reduced the activation of glial cells in spinal cord dorsal horn
      • Yang L
      • Wang S-H
      • Hu Y
      • Sui Y-F
      • Peng T
      • Guo T-C
      Effects of repetitive transcranial magnetic stimulation on astrocytes proliferation and nNOS expression in neuropathic pain rats.
      and decreased BDNF concentrations both in the central nervous system and in blood serum.
      • Filho PRM
      • Vercelino R
      • Cioato SG
      • Medeiros LF
      • de Oliveira C
      • Scarabelot VL
      • Souza A
      • Rozisky JR
      • Quevedo A da S
      • Adachi LNS
      • Sanches PRS
      • Fregni F
      • Caumo W
      • Torres ILS
      Transcranial direct current stimulation (tDCS) reverts behavioral alterations and brainstem BDNF level increase induced by neuropathic pain model: Long-lasting effect.
      Three studies reported on the effect of TENS therapy. TENS could not reduce proinflammatory cytokines (TNF-a) in the sciatic nerve,
      • Lin H-T
      • Chiu C-C
      • Wang J-J
      • Hung C-H
      • Chen Y-W
      High frequency transcutaneous electrical nerve stimulation with diphenidol administration results in an additive antiallodynic effect in rats following chronic constriction injury.
      in fact 1 study reported an increase in that biomarker.
      • Su H-L
      • Chiang C-Y
      • Lu Z-H
      • Cheng F-C
      • Chen C-J
      • Sheu M-L
      • Sheehan J
      • Pan H-C
      Late administration of high-frequency electrical stimulation increases nerve regeneration without aggravating neuropathic pain in a nerve crush injury.
      However, TENS did reduce the concentration of proinflammatory cytokines in the spinal cord.
      • Matsuo H
      • Uchida K
      • Nakajima H
      • Guerrero AR
      • Watanabe S
      • Takeura N
      • Sugita D
      • Shimada S
      • Nakatsuka T
      • Baba H
      Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.
      The glial activity in the spinal cord was reduced after the application of TENS, and the expression of opioid receptors increased in the same location.
      • Matsuo H
      • Uchida K
      • Nakajima H
      • Guerrero AR
      • Watanabe S
      • Takeura N
      • Sugita D
      • Shimada S
      • Nakatsuka T
      • Baba H
      Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.
      Contradictory results were reported regarding the presence of excitatory neurotransmitters in the spinal cord.
      • Somers DL
      • Clemente FR
      Contralateral high or a combination of high- and low-frequency transcutaneous electrical nerve stimulation reduces mechanical allodynia and alters dorsal horn neurotransmitter content in neuropathic rats.
      The pulse electromagnetic field was consistent in modulating the cytokine concentrations, in both the spinal cord and the peripheral nerve tissue that caused the injury.
      • Mert T
      • Altun I
      • Celik A
      • Surer T
      • Gunay I
      Modulation of cytokine levels in ameliorative effects of pulsed magnetic field on an experimental model of Chronic Constriction Injury.
      ,
      • Mert T
      • Gisi G
      • Celik A
      • Baran F
      • Uremis MM
      • Gunay I
      Frequency-dependent effects of sequenced pulsed magnetic field on experimental diabetic neuropathy.

      Electro-Acupuncture

      Electroacupuncture reduced the concentrations of proinflammatory cykines. The doses reported ranged from 1 to 2 mA, fluctuating between 2 and 100 Hz, 1.05 to 2.85 milli seconds for 30 minutes. Most of the changes seem to occur in the dorsal horn
      • Liu H
      • Ma Y
      • Liu J
      • Guo Z
      • Yan W
      • Wen S
      • Zhao Q
      • Guo X
      • Zhang X
      • Sheng Q
      Therapeutic effect of electroacupuncture on rats with neuropathic pain.
      ,
      • Wang J
      • Gao Y
      • Chen S
      • Duanmu C
      • Zhang J
      • Feng X
      • Yan Y
      • Liu J
      • Litscher G
      The effect of repeated electroacupuncture analgesia on neurotrophic and cytokine factors in neuropathic pain rats.
      ,
      • Wang Y
      • Jiang Q
      • Xia Y yang
      • Huang Z hua
      • Huang C
      Involvement of α7nAChR in electroacupuncture relieving neuropathic pain in the spinal cord of rat with spared nerve injury.
      ,
      • Wang Y
      • Xue M
      • Xia YY
      • Jiang Q
      • Huang ZH
      • Huang C
      Electroacupuncture treatment suppresses transcription factor IRF8 in spinal cord of rats with spared nerve injury.
      ,
      • Xu J
      • Chen X-M
      • Zheng B-J
      • Wang X-R
      Electroacupuncture relieves nerve injury-induced pain hypersensitivity via the inhibition of spinal P2×7 receptor-positive microglia.
      ,
      • Zhao YX
      • Yao MJ
      • Liu Q
      • Xin JJ
      • Gao JH
      • Yu XC
      Electroacupuncture treatment attenuates paclitaxel-induced neuropathic pain in rats via inhibiting spinal glia and the TLR4/NF-κB pathway.
      although changes in the nerve,

      Cha MH, Nam TS, Kwak Y, Lee H, Lee BH: Changes in cytokine expression after electroacupuncture in neuropathic rats. Evid-based Complement Altern Med 2012.

      ,
      • Wang X
      • Li Q
      • Han X
      • Gong M
      • Yu Z
      • Xu B
      Electroacupuncture alleviates diabetic peripheral neuropathy by regulating glycolipid-related GLO/AGEs/RAGE axis.
      blood,
      • Gao Y-H
      • Wang J-Y
      • Qiao L-N
      • Chen S-P
      • Tan L-H
      • Xu Q-L
      • Liu J-L
      NK cells mediate the cumulative analgesic effect of electroacupuncture in a rat model of neuropathic pain.
      and DRG
      • Wenzhan T
      • Wansheng W
      • Haiyan X
      • Rong H
      • Liping G
      • Songhe J
      Regulation of neurotrophin-3 and interleukin-1 β and inhibition of spinal glial activation contribute to the analgesic effect of electroacupuncture in chronic neuropathic pain states of rats.
      were also reported. In contrast, four articles did not find changes in cytokine concentrations following electroacupuncture.

      Cha MH, Nam TS, Kwak Y, Lee H, Lee BH: Changes in cytokine expression after electroacupuncture in neuropathic rats. Evid-based Complement Altern Med 2012.

      ,
      • Gao Y-H
      • Wang J-Y
      • Qiao L-N
      • Chen S-P
      • Tan L-H
      • Xu Q-L
      • Liu J-L
      NK cells mediate the cumulative analgesic effect of electroacupuncture in a rat model of neuropathic pain.
      ,
      • Liang Y
      • Qiu Y
      • Du J
      • Liu J
      • Fang J
      • Zhu J
      • Fang J
      Inhibition of spinal microglia and astrocytes contributes to the anti-allodynic effect of electroacupuncture in neuropathic pain induced by spinal nerve ligation.
      ,
      • Wang J
      • Gao Y
      • Chen S
      • Duanmu C
      • Zhang J
      • Feng X
      • Yan Y
      • Liu J
      • Litscher G
      The effect of repeated electroacupuncture analgesia on neurotrophic and cytokine factors in neuropathic pain rats.
      The effect of electroacupuncture reported on neurotrophins has been mixed. Articles reported decreased concentrations of nerve growth factors (NGF and BDNF) in dorsal root ganglia and spinal cord dorsal horn
      • Manni L
      • Florenzano F
      • Aloe L
      Electroacupuncture counteracts the development of thermal hyperalgesia and the alteration of nerve growth factor and sensory neuromodulators induced by streptozotocin in adult rats.
      ,
      • Nori SL
      • Rocco ML
      • Florenzano F
      • Ciotti MT
      • Aloe L
      • Manni L
      Increased nerve growth factor signaling in sensory neurons of early diabetic rats is corrected by electroacupuncture.
      ,
      • Wang J
      • Gao Y
      • Chen S
      • Duanmu C
      • Zhang J
      • Feng X
      • Yan Y
      • Liu J
      • Litscher G
      The effect of repeated electroacupuncture analgesia on neurotrophic and cytokine factors in neuropathic pain rats.
      ,
      • Wen-Zhan T
      • Si-SI L
      • Xia J
      • Xin-Ru Q
      • Guan-Hu Y
      • Peng-Peng G
      • Bin L
      • Song-HE J
      Effect of electro-acupuncture on the BDNF-TrkB pathway in the spinal cord of CCI rats.
      while others obtained significant increases in the same anatomical sites for NGF,
      • Wenzhan T
      • Wansheng W
      • Haiyan X
      • Rong H
      • Liping G
      • Songhe J
      Regulation of neurotrophin-3 and interleukin-1 β and inhibition of spinal glial activation contribute to the analgesic effect of electroacupuncture in chronic neuropathic pain states of rats.
      BDNF,
      • Chunchun X
      • Lei X
      • Xia L
      • Jianfeng C
      • Zhen G
      • Kaiqiang W
      Analgesic mechanism of electroacupuncture in a rat L5 spinal nerve ligation model.
      and GDNF.
      • Dong Z-Q
      • Ma F
      • Xie H
      • Wang Y-Q
      • Wu G-C
      Changes of expression of glial cell line-derived neurotrophic factor and its receptor in dorsal root ganglions and spinal dorsal horn during electroacupuncture treatment in neuropathic pain rats.
      These differences may be due to the starting times and duration of treatment. It seems that most of the articles that reported a decreased concentration
      • Manni L
      • Florenzano F
      • Aloe L
      Electroacupuncture counteracts the development of thermal hyperalgesia and the alteration of nerve growth factor and sensory neuromodulators induced by streptozotocin in adult rats.
      ,
      • Nori SL
      • Rocco ML
      • Florenzano F
      • Ciotti MT
      • Aloe L
      • Manni L
      Increased nerve growth factor signaling in sensory neurons of early diabetic rats is corrected by electroacupuncture.
      ,
      • Wang J
      • Gao Y
      • Chen S
      • Duanmu C
      • Zhang J
      • Feng X
      • Yan Y
      • Liu J
      • Litscher G
      The effect of repeated electroacupuncture analgesia on neurotrophic and cytokine factors in neuropathic pain rats.
      ,
      • Wen-Zhan T
      • Si-SI L
      • Xia J
      • Xin-Ru Q
      • Guan-Hu Y
      • Peng-Peng G
      • Bin L
      • Song-HE J
      Effect of electro-acupuncture on the BDNF-TrkB pathway in the spinal cord of CCI rats.
      had a treatment duration greater or equal to 2 weeks. In contrast those that increased pain markers expression only treated the animals for 1 week.
      • Chunchun X
      • Lei X
      • Xia L
      • Jianfeng C
      • Zhen G
      • Kaiqiang W
      Analgesic mechanism of electroacupuncture in a rat L5 spinal nerve ligation model.
      ,
      • Wenzhan T
      • Wansheng W
      • Haiyan X
      • Rong H
      • Liping G
      • Songhe J
      Regulation of neurotrophin-3 and interleukin-1 β and inhibition of spinal glial activation contribute to the analgesic effect of electroacupuncture in chronic neuropathic pain states of rats.

      Acupuncture

      The three acupuncture articles included were very heterogeneous. Wang et al
      • Wang Y
      • Yuan H
      • Xu D
      • WY W
      Balance acupuncture: an experimental study on the effectiveness of treating radicular pain in a lumbar disc herniation rat model.
      and Tang et al
      • Tang HY
      • Wang FJ
      • Ma JL
      • Wang H
      • Shen GM
      • Jiang AJ
      Acupuncture attenuates the development of diabetic peripheral neuralgia by regulating P2×4 expression and inflammation in rat spinal microglia.
      found a significant decrease in the concentrations of cytokines. Tang et al does not report the first day of intervention. While Wang et al performed the treatment 1 day after surgery and for a period of 14 days,
      • Wang Y
      • Yuan H
      • Xu D
      • WY W
      Balance acupuncture: an experimental study on the effectiveness of treating radicular pain in a lumbar disc herniation rat model.
      Chang et al started the intervention 24 days after surgery, during a period of 5 days.
      • Chang IA
      • Namgung U
      Induction of regenerative responses of injured sciatic nerve by pharmacopuncture therapy in rats.
      The location of biomarker measurement were different; Wang et al measured cytokines in the blood meanwhile Tang et al measured in the sciatic nerve, Chang et al measured Cdc2 and P-vim in the sciatic nerve and DRG with no difference after treatment.
      • Chang IA
      • Namgung U
      Induction of regenerative responses of injured sciatic nerve by pharmacopuncture therapy in rats.
      Tang performed the treatment for 20 minutes in contrast to the others two articles, that did the same 30-minute daily dose was applied, but the duration of treatment varied between 1 and 2 weeks.

      Discussion

      This systematic review summarizes the results of 85 studies that report the influence of different types of physiotherapy modalities on biomarkers of peripheral neuropathic pain in pre-clinical models. The 2 most studied interventions were electro-acupuncture and exercise, with neural mobilization, joint mobilization and physical agents being less commonly studied. The most frequently measured biomarker group was related to the neuro-immune system, specifically cytokines. The dorsal horn is the anatomical site where biomarkers were measured most frequently. Most studies, despite their heterogeneous nature, report significant postintervention changes of the biomarkers of neuropathic pain. Our findings indicate that physiotherapy interventions downregulate the expression of pronociceptive (eg. immune system or neurotrophins) markers and upregulate the expression of markers that dampen neuropathic pain (eg. opioid system). However, risk of bias was high in 97.5% of studies.
      Our findings about the most common model is similar to previous reviews about preclinical models of NP were traumatic injury (78.9%) is the most commun.
      • Andrew SCR
      • Finnerup NB.
      • Kemp HI
      • Gillian L
      Currie and RB: Sensory profiling in animal models of neuropathic pain: A call for back-translation.
      Although neuropathic pain induced by chemotherapy
      • Song SJ
      • Min J
      • Suh SY
      • Jung SH
      • Hahn HJ
      • Im SA
      • Lee JY
      Incidence of taxane-induced peripheral neuropathy receiving treatment and prescription patterns in patients with breast cancer.
      or diabetic painful neuropathy are growing problems,
      • Abbott CA
      • Malik RA
      • Van Ross ERE
      • Kulkarni J
      • Boulton AJM
      Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K.
      the models of neuropathic pain induced by chemotherapy and diabetic neuropathy have not been used very often in preclinical physiotherapy studies (2.5% and 11.1%, respectively).

      Effects of Physiotherapy

      Exercise was one of the main interventions studied, specifically swimming and running (treadmill). It is well established that aerobic exercise induces analgesic effects in preclinical models.
      • Guo JB
      • Chen BL
      • Wang Y
      • Zhu Y
      • Song G
      • Yang Z
      • Zheng YL
      • Wang XQ
      • Chen PJ
      Meta-analysis of the effect of exercise on neuropathic pain induced by peripheral nerve injury in rat models.
      Our results demonstrate that aerobic exercise has promising effects on biomarker modulation in neuropathic pain. There seems to be a consistent effect of aerobic exercise on the modulation of markers of neuro-inflammation in the peripheral and central nervous system. Other biomarkers, such as neurotrophins and neurotransmitters are also modulated by exercise. Of note, studies which did not demonstrate an effect on biomarkers used exercise duration of less than 40 minutes,
      • Almeida C
      • DeMaman A
      • Kusuda R
      • Cadetti F
      • Ravanelli MI
      • Queiroz AL
      • Sousa TA
      • Zanon S
      • Silveira LR
      • Lucas G
      Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain.
      ,
      • Coradini JG
      • Kunz RI
      • Kakihata CMM
      • Errero TK
      • Bonfleur ML
      • de Fátima Chasko Ribeiro L
      • Brancalhão RMC
      • Bertolini GRF
      Swimming does not alter nociception threshold in obese rats submitted to median nerve compression.
      perhaps insufficient time to generate changes. In contrast, studies showing an effect on biomarkers included sessions with a duration between 60 and 90 minutes.
      • Chen Y-W
      • Li Y-T
      • Chen YC
      • Li Z-Y
      • Hung C-H
      Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve.
      ,
      • TIAN J
      • YU T
      • XU Y
      • PU S
      • LV Y
      • ZHANG XIN
      • DU D
      Swimming training reduces neuroma pain by regulating neurotrophins.
      For treadmill running, only 1 article did not find changes after intervention.
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
      In this experiment the animals ran until exhaustion,
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
      while in the others it was of a fixed duration.
      • Bobinski F
      • Teixeira JM
      • Sluka KA
      • Santos ARS
      Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain.
      ,
      • Ching-Hsia H
      • Po-Ching H
      • Jann-Inn T
      • Jhi-Joung W
      • Yu-Wen C
      Therapeutic ultrasound and treadmill training suppress peripheral nerve injury-induced pain in rats.
      ,
      • Cobianchi S
      • Marinelli S
      • Florenzano F
      • Pavone F
      • Luvisetto S
      Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
      ,
      • Kami K
      • Taguchi S
      • Tajima F
      • Senba E
      Histone acetylation in microglia contributes to exercise-induced hypoalgesia in neuropathic pain model mice.
      ,
      • Lopez-Alvarez VM
      • Modol L
      • Navarro X
      • Cobianchi S
      Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury.
      It could thus be speculated that reaching exhaustion may counteract the positive effects of physical activity in regulating glial cell activity.
      Neural Mobilizations have shown efficacy in human trials of patients with referred leg or arm pain of neural origin,
      • Basson A
      • Olivier B
      • Ellis R
      • Coppieters M
      • Stewart A
      • Mudzi W
      The effectiveness of neural mobilization for neuromusculoskeletal conditions: A systematic review and meta-analysis.
      however their exact mechanisms of action remain speculative. In line with findings in animal models,
      • Santos FM
      • Silva JT
      • Rocha IRC
      • Martins DO
      • Chacur M
      Non-pharmacological treatment affects neuropeptide expression in neuropathic pain model.
      ,
      • Zhu GC
      • Tsai KL
      • Chen YW
      • Hung CH
      Neural mobilization attenuates mechanical allodynia and decreases proinflammatory cytokine concentrations in rats with painful diabetic neuropathy.
      neural mobilizations improve mechanical hyperalgesia in patients after neural mobilization intervention.
      • Bialosky JE
      • Bishop MD
      • Price DD
      • Robinson ME
      • Vincent KR
      • George SZ
      A randomized sham-controlled trial of a neurodynamic technique in the treatment of carpal tunnel syndrome.
      Our findings indicate that neural mobilizations may exert their beneficial effect through modulating neuroinflammation, opioid system, and neurotrophins. The ability of neural mobilization to disperse fluids has been reported with cadaveric models.
      • Boudier-Revéret M
      • Gilbert KK
      • Allégue DR
      • Moussadyk M
      • Brismée JM
      • Sizer PS
      • Feipel V
      • Dugailly PM
      • Sobczak S
      Effect of neurodynamic mobilization on fluid dispersion in median nerve at the level of the carpal tunnel: A cadaveric study.
      In patients, there is also some indication that neuroinflammation may be a target. Schmid et al reported a reduction of intreanueral edema after 1 week of neural mobilization in patients with carpal tunnel syndrome.
      • Schmid AB
      • Elliott JM
      • Strudwick MW
      • Little M
      • Coppieters MW
      Effect of splinting and exercise on intraneural edema of the median nerve in carpal tunnel syndrome-an MRI study to reveal therapeutic mechanisms.
      Although Joint mobilization techniques are often used, they seem to have only short term analgesic effects in humans.
      • Bialosky JE
      • Bishop MD
      • Robinson ME
      • Jr GZ
      • George SZ
      Spinal manipulative therapy has an immediate effect on thermal pain sensitivity in people with low back pain: A randomized controlled trial.
      ,
      • Schmid A
      • Brunner F
      • Wright A
      • Bachmann LM
      Paradigm shift in manual therapy? Evidence for a central nervous system component in the response to passive cervical joint mobilisation.
      In addition they are not usually used for neuropathic pain, but for nociceptive pain.
      • Bialosky JE
      • Bishop MD
      • Price DD
      • Robinson ME
      • George SZ
      The mechanisms of manual therapy in the treatment of musculoskeletal pain: A comprehensive model.
      ,
      • Moss P
      • Sluka K
      • Wright A
      The initial effects of knee joint mobilization on osteoarthritic hyperalgesia.
      Both preclinical studies included in our systematic review reported a decrease of mechanical hyperalgesia after the interventions.
      • Martins DF
      • Mazzardo-Martins L
      • Gadotti VM
      • Nascimento FP
      • Lima DAN
      • Speckhann B
      • Favretto GA
      • Bobinski F
      • Cargnin-Ferreira E
      • Bressan E
      • Dutra RC
      • Calixto JB
      • Santos ARS
      Ankle joint mobilization reduces axonotmesis-induced neuropathic pain and glial activation in the spinal cord and enhances nerve regeneration in rats.
      ,
      • Song XJ
      • Huang ZJ
      • Song WB
      • Song XS
      • Fuhr AF
      • Rosner AL
      • Ndtan H
      • Rupert RL
      Attenuation effect of spinal manipulation on neuropathic and postoperative pain through activating endogenous anti-inflammatory cytokine interleukin 10 in rat spinal cord.
      Similarly, Krouwel et al reported an increase on the pain pressure thresholds in humans after a lumbar joint mobilization.
      • Krouwel O
      • Hebron C
      • Willett E
      An investigation into the potential hypoalgesic effects of different amplitudes of PA mobilisations on the lumbar spine as measured by pressure pain thresholds (PPT).
      ,
      • Schmid A
      • Brunner F
      • Wright A
      • Bachmann LM
      Paradigm shift in manual therapy? Evidence for a central nervous system component in the response to passive cervical joint mobilisation.
      Interestingly, our data indicate that joint mobilization may exert their beneficial effects through modulation of glial cells and cytokines. However, only two articles were included, both using different techniques which make it difficult to draw firm conclusions.
      Physical agents are often used clinically as analgesic treatments. However, their clinical benefit remains contradictory. For instance, a Cochrane review about the use of TENS in adults with neuropathic pain could not draw firm conclusions whether TENS is effective for pain control due to the very low quality of the evidence.
      • Gibson W
      • Wand BM
      • O'Connell NE
      Transcutaneous electrical nerve stimulation (TENS) for neuropathic pain in adults.
      Another review from Akyuz et al conclude that physical modalities such as ultrasound or laser are not effective for the treatment of neuropathic pain when applied alone.
      • Akyuz G
      • Kenis O
      Physical therapy modalities and rehabilitation techniques in the management of neuropathic pain.
      Our data suggest that physical agents mainly seems to modulate neuropathic pain through regulation of neuroinflammation, such as a downregulation of TNF and IL-1β which are associated with the maintenance of neuropathic pain after peripheral injury.
      • Scholz J
      • Woolf CJ
      The neuropathic pain triad: Neurons, immune cells and glia.
      Nevertheless, physical agents could also modulate other biomarkers, for instance neurotrophins or neurotransmitters.
      Electroacupuncture has shown some evidence in reducing pain in patients with osteoarthritis mediated by β-endorphins.
      • Ahsin S
      • Saleem S
      • Bhatti AM
      • Iles RK
      • Aslam M
      Clinical and endocrinological changes after electro-acupuncture treatment in patients with osteoarthritis of the knee.
      Human evidence for the effect of electroacupuncture on neuropathic pain remains controversial. Penza et al did not find pain improvements following electroacupuncture treatment in patients with neuropathic pain
      • Penza P
      • Bricchi M
      • Scola A
      • Campanella A
      • Lauria G
      Electroacupuncture is not effective in chronic painful neuropathies.
      whereas Galantino et al reported some improvement in patients with human immunodeficiency virus-related peripheral neuropathy.
      • Galantino MLA
      • Eke-Okoro ST
      • Findley TW
      • Condoluci D
      Use of noninvasive electroacupuncture for the treatment of HIV-related peripheral neuropathy: A pilot study.
      In both reports the number of patients included was small, so these results remain preliminary. Our findings indicate that electroacupuncture may exert beneficial effects through modulating neuroinflammation, regulating neurotrophins and neurotransmitters as well as decreasing ATP and ion channels, such as TRPV1.
      • Chen X-M
      • Xu J
      • Song J-G
      • Zheng B-J
      • Wang X-R
      Electroacupuncture inhibits excessive interferon-γ evoked up-regulation of P2×4 receptor in spinal microglia in a CCI rat model for neuropathic pain.
      ,
      • Li Y
      • Yin C
      • Li X
      • Liu B
      • Wang J
      • Zheng X
      • Shao X
      • Liang Y
      • Du J
      • Fang J
      • Liu B
      Electroacupuncture alleviates paclitaxel-induced peripheral neuropathic pain in rats via suppressing TLR4 signaling and TRPV1 upregulation in sensory neurons.
      • Liang Y
      • Du J-Y
      • Qiu Y-J
      • Fang J-F
      • Liu J
      • Fang J-Q
      Electroacupuncture attenuates spinal nerve ligation-induced microglial activation mediated by p38 mitogen-activated protein kinase.
      • Liang Y
      • Qiu Y
      • Du J
      • Liu J
      • Fang J
      • Zhu J
      • Fang J
      Inhibition of spinal microglia and astrocytes contributes to the anti-allodynic effect of electroacupuncture in neuropathic pain induced by spinal nerve ligation.
      ,
      • Wang J
      • Gao Y
      • Chen S
      • Duanmu C
      • Zhang J
      • Feng X
      • Yan Y
      • Liu J
      • Litscher G
      The effect of repeated electroacupuncture analgesia on neurotrophic and cytokine factors in neuropathic pain rats.
      ,
      • Wang W-S
      • Tu W-Z
      • Cheng R-D
      • He R
      • Ruan L-H
      • Zhang L
      • Gong Y-S
      • Fan X-F
      • Hu J
      • Cheng B
      • Lai Y-P
      • Zou E-M
      • Jiang S-H
      Electroacupuncture and A-317491 depress the transmission of pain on primary afferent mediated by the P2×3 receptor in rats with chronic neuropathic pain states.
      ,
      • Wenzhan T
      • Wansheng W
      • Haiyan X
      • Rong H
      • Liping G
      • Songhe J
      Regulation of neurotrophin-3 and interleukin-1 β and inhibition of spinal glial activation contribute to the analgesic effect of electroacupuncture in chronic neuropathic pain states of rats.
      • Xia Y
      • Xue M
      • Wang Y
      • Huang Z
      • Huang C
      Electroacupuncture alleviates spared nerve injury-induced neuropathic pain and modulates HMGBI/NF-kappa B signaling pathway in the spinal cord.
      • Xu J
      • Chen X-M
      • Zheng B-J
      • Wang X-R
      Electroacupuncture relieves nerve injury-induced pain hypersensitivity via the inhibition of spinal P2×7 receptor-positive microglia.
      ,
      • Zhang M
      • Dai Q
      • Liang D
      • Li D
      • Chen S
      • Chen S
      • Han K
      • Huang L
      • Wang J
      Involvement of adenosine A1 receptor in electroacupuncture-mediated inhibition of astrocyte activation during neuropathic pain.
      Another possible mechanism is that this type of electrical stimulation may be activating the endogenous opioid system by the release of enkephalins and b-endorphins.
      • Han J-S
      Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies.
      As we only identified three articles about acupuncture, it is difficult to hypothesize about its mechanisms of action. Preliminary data suggest that similar to electro-acupuncture this technique might modulate the activation of the neuro-immune system,
      • Chang IA
      • Namgung U
      Induction of regenerative responses of injured sciatic nerve by pharmacopuncture therapy in rats.
      ,
      • Tang HY
      • Wang FJ
      • Ma JL
      • Wang H
      • Shen GM
      • Jiang AJ
      Acupuncture attenuates the development of diabetic peripheral neuralgia by regulating P2×4 expression and inflammation in rat spinal microglia.
      ,
      • Wang Y
      • Yuan H
      • Xu D
      • WY W
      Balance acupuncture: an experimental study on the effectiveness of treating radicular pain in a lumbar disc herniation rat model.
      but further research is needed. In line with our preclinical findings, a Cochrane review about the use of acupuncture in humans with any type of neuropathic pain reports limited evidence.
      • Ju ZY
      • Wang K
      • Cui HS
      • Yao Y
      • Liu SM
      • Zhou J
      • Chen TY
      • Xia J
      Acupuncture for neuropathic pain in adults.
      Another review about acupuncture and its effect on pain could also not establish a clear relationship between the technique and the analgesics effects in humans.
      • Madsen MV
      • Gøtzsche PC
      • Hróbjartsson A
      Acupuncture treatment for pain: Systematic review of randomised clinical trials with acupuncture, placebo acupuncture, and no acupuncture groups.

      Implications for Humans

      The importance of specific biomarkers to maintain neuropathic pain is not only clear in preclinical models,
      • Clark AK
      • Old EA
      • Malcangio M
      Neuropathic pain and cytokines: Current perspectives.
      but also in humans.
      • Sommer C
      • Leinders M
      • Üçeyler N
      Inflammation in the pathophysiology of neuropathic pain.
      Our findings suggest that Physiotherapy can modulate biomarkers related to neuropathic pain in preclinical models. Although the most studied biomarkers related to the immune system and neurotrophins, this review identified other targets, such as neurotransmitters or the opioid system. In recent years, several publications have reported the possible relationship between the presence of neuropathic pain and some of the reported biomarkers of humans. For instance, neuroinflammation is thought to play a crucial role in the generation and maintenance of neuropathic pain in preclinical models
      • Austin PJ
      • Moalem-Taylor G
      The neuro-immune balance in neuropathic pain: Involvement of inflammatory immune cells, immune-like glial cells and cytokines.
      Similarly, there is a growing body of evidence confirming the importance of neuroinflammation in neuropathic pain in humans. Inflammation in the pathophysiology of neuropathic pain
      • Sommer C
      • Leinders M
      • Üçeyler N
      Inflammation in the pathophysiology of neuropathic pain.
      This is apparent both in patients with focal nerve injuries,
      • Held M
      • Karl F
      • Vlckova E
      • Rajdova A
      • Escolano-Lozano F
      • Stetter C
      • Bharti R
      • Förstner KU
      • Leinders M
      • Dušek L
      • Birklein F
      • Bednarik J
      • Sommer C
      • Üçeyler N
      Sensory profiles and immune-related expression patterns of patients with and without neuropathic pain after peripheral nerve lesion.
      but also in patients with polyneuropathies.
      • Hubertus Köller M.D.
      • Bernd C.
      • Kieseier M.D.
      • Sebastian Jander MD
      • Hans-Peter Hartung MD
      Chronic inflammatory demyelinating polyneuropathy.
      ,
      • Ziegler D
      • Strom A
      • Bönhof GJ
      • Kannenberg JM
      • Heier M
      • Rathmann W
      • Peters A
      • Meisinger C
      • Roden M
      • Thorand B
      • Herder C
      Deficits in systemic biomarkers of neuroinflammation and growth factors promoting nerve regeneration in patients with type 2 diabetes and polyneuropathy.
      As such, our findings indicate that physiotherapy can modulate biomarkers that are relevant in patients with neuropathic pain.
      In addition to the neuroimmune system, other systems may influence the presence of NP. For example, neurotrophins have been implicated with neuropathic pain. For Instance, NGF acts as a pathogenic pain mediator
      • Herzberg U
      • Eliav E
      • Dorsey JM
      • Gracely RH
      • Kopin IJ
      NGF involvement in pain induced by chronic constriction injury of the rat sciatic nerve.
      and also in humans, high levels of NGF have been associated with pain.
      • Svensson P
      • Cairns BE
      • Wang K
      • Arendt-Nielsen L
      Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia.
      BDNF shows similar hyperalgesic effects and its presence in the dorsal root ganglia and the spinal cord correlate with neuropathic pain behaviour.
      • Siniscalco D
      • Giordano C
      • Rossi F
      • Maione S
      • de Novellis V
      Role of neurotrophins in neuropathic pain.
      The dysfunction of the opioid system has been described in preclinical
      • Porreca F
      • Tang QB
      • Bian D
      • Riedl M
      • Eide R
      • Lai J
      Spinal opioid mu receptor expression in lumbar spinal cord of rats following nerve injury.
      and in humans with NP.
      • DosSantos MF
      • Martikainen IK
      • Nascimento TD
      • Love TM
      • Deboer MD
      • Maslowski EC
      • Monteiro AA
      • Vincent MB
      • Zubieta JK
      • DaSilva AF
      Reduced basal ganglia μ-opioid receptor availability in trigeminal neuropathic pain: A pilot study.
      And other indirect measure from the opioid system is the conditioned pain modulation which is mediated by the endogenous opioid system.
      • Vigotsky AD
      • Bruhns RP
      The role of descending modulation in manual therapy and its analgesic Implications: A narrative review.
      This type of alteration has been reported in patients with different types of NP, such as complex regional pain syndrome
      • Seifert F
      • Kiefer G
      • Decol R
      • Schmelz M
      • Maihöfner C
      Differential endogenous pain modulation in complex-regional pain syndrome.
      or carpal tunnel syndrome.
      • Soon B
      • Vicenzino B
      • Schmid AB
      • Coppieters MW
      Facilitatory and inhibitory pain mechanisms are altered in patients with carpal tunnel syndrome.
      These 2 systems look like a promising target which required further investigation in human trials.
      So far, pharmacological management has been the first line of treatment for NP in humans. Tricyclic antidepressants (eg, amitriptyline), and serotonin-noradrenaline reuptake inhibitors (eg, duloxetine) or anticonvulsants (eg, pregabalin) have been use as first line option.
      • Colloca L
      • Ludman T
      • Bouhassira D
      • Baron R
      • Dickenson AH
      • Yarnitsky D
      • Freeman R
      • Truini A
      • Attal N
      • Finnerup NB
      • Eccleston C
      • Kalso E
      • Bennett DL
      • Dworkin RH
      • Raja SN
      Neuropathic pain.
      Also opioids, like tramadol have been use to target the opioid system.

      Connor ABO, Dworkin RH: Treatment of neuropathic pain: An overview of recent guidelines 122:S22–32, 2009.

      Even Combination therapy have been used in these kind of patients, for instance the use mixed of morphine and gabapentin provided better pain relief together but that gain was also modest.
      • Gilron I
      • Bailey JM
      • Tu D
      • Holden RR
      • Weaver DF
      • Houlden RL
      Morphine, gabapentin, or their combination for neuropathic pain.
      Despite of this evidence, some trials have report controversial results
      • Baron R
      • Freynhagen R
      • Tölle TR
      • Cloutier C
      • Leon T
      • Murphy TK
      • Phillips K
      The efficacy and safety of pregabalin in the treatment of neuropathic pain associated with chronic lumbosacral radiculopathy.
      ,
      • Hui ACF
      • Wong SM
      • Leung HW
      • Man BL
      • Yu E
      • Wong LKS
      Gabapentin for the treatment of carpal tunnel syndrome: A randomized controlled trial.
      in addition of the concerns about side effects reported of long term used
      • Jensen TS
      • Madsen CS
      • Finnerup NB
      Pharmacology and treatment of neuropathic pains.
      advises on looking for new, safer treatment options.
      Future targets to investigate are the endogenous cannabinoids, such as CB2 receptor which recently have been shown to increase hypersensitivity in models of neuropathic pain
      • Mert T
      • Gisi G
      • Celik A
      • Baran F
      • Uremis MM
      • Gunay I
      Frequency-dependent effects of sequenced pulsed magnetic field on experimental diabetic neuropathy.
      and we have not found this to have been evaluated in physiotherapy studies.
      Whereas the results of this study seem to suggest promising effects of biomarker modulation of physiotherapy interventions for peripheral neuropathic pain, these findings cannot be directly translated to understand the mechanism of these therapies in humans. Nevertheless, these findings can provide guidance on the type and design of future physiotherapy interventions in clinical trials.
      One of the most recommended treatment option for the treatment of neuropathic pain, a part of pharmacology, is exercise.
      National Institute for Health and Care Excellence
      Low back pain and sciatica in over 16s: assessment and management (NG59).
      ,
      • Zhang YH
      • Hu HY
      • Xiong YC
      • Peng C
      • Hu L
      • Kong YZ
      • Wang YL
      • Guo JB
      • Bi S
      • Li TS
      • Ao LJ
      • Wang CH
      • Bai YL
      • Fang L
      • Ma C
      • Liao LR
      • Liu H
      • Zhu Y
      • Zhang ZJ
      • Liu CL
      • Fang GE
      • Wang XQ
      Exercise for neuropathic pain: A systematic review and expert consensus.
      In humans is well establish that the hypoalgesic effects are correlated with the intensity or the prescribed dose.
      • Naugle KM
      • Naugle KE
      • Fillingim RB
      • Samuels B
      • Riley JL
      Intensity thresholds for aerobic exercise-induced hypoalgesia.
      ,
      • Polaski AM
      • Phelps AL
      • Kostek MC
      • Szucs KA
      • Kolber BJ
      Exercise-induced hypoalgesia: A meta-analysis of exercise dosing for the treatment of chronic pain.
      ,
      • Vaegter HB
      • Bjerregaard LK
      • Redin MM
      • Rasmussen SH
      • Graven-Nielsen T
      Hypoalgesia after bicycling at lactate threshold is reliable between sessions.
      Only three articles analyzed in this review reported the intensity of the intervention.
      • Bobinski F
      • Ferreira TAA
      • Córdova MM
      • Dombrowski PA
      • da Cunha C
      • Santo CC
      • Poli A
      • Pires RGW
      • Martins-Silva C
      • Sluka KA
      • Santos ARS
      Role of brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic pain after sciatic nerve injury in mice.
      • Bobinski F
      • Martins DF
      • Bratti T
      • Mazzardo-Martins L
      • Winkelmann-Duarte EC
      • Guglielmo LGA
      • Santos ARS
      Neuroprotective and neuroregenerative effects of low-intensity aerobic exercise on sciatic nerve crush injury in mice.
      • Bobinski F
      • Teixeira JM
      • Sluka KA
      • Santos ARS
      Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain.
      The 3 reports used low intensity prescription and they reported changes in biomarkers concentrations in both, locally and remotely. This is intriguing since, in humans, has been reported central activation mechanisms only with high intensity.
      • Vaegter HB
      • Bjerregaard LK
      • Redin MM
      • Rasmussen SH
      • Graven-Nielsen T
      Hypoalgesia after bicycling at lactate threshold is reliable between sessions.
      Future research taking the intensity into account should be done.

      Limitations

      We have identified some limitations in our review. As we have not extracted the data from behavioral assessments, we cannot classify the interventions and the posterior analysis by the potential neuropathic pain mechanisms. Only studies written in English were included after the selection process. The heterogeneity of the measurement methods as well as the large number of different biomarkers analyzed challenges the interpretation. Of note, 92.5% of studies only included male rats. It is well established that pain behavior and underlying mechanisms differ according to sex,
      • Rosen S
      • Ham B
      • Mogil JS
      Sex differences in neuroimmunity and pain.
      thus limiting the generalizability of our findings. Importantly, risk of bias was high and reporting according to the ARRIVE guidelines was poor in the majority of studies. The inconsistent reporting of summary statistics prevented a meta-analysis. Poor reporting and methodological quality have been identified as major challenges in preclinical research including in the pain field.
      • Macleod MR
      • Fisher M
      • O'Collins V
      • Sena ES
      • Dirnagl U
      • Bath PMW
      • Buchan A
      • van der Worp HB
      • Traystman R
      • Minematsu K
      • Donnan GA
      • Howells DW
      Good laboratory practice: preventing introduction of bias at the bench.
      ,
      • Vollert J
      • Schenker E
      • Macleod M
      • Bespalov A
      • Wuerbel H
      • Michel M
      • Dirnagl U
      • Potschka H
      • Waldron A-M
      • Wever K
      • Steckler T
      • van de Casteele T
      • Altevogt B
      • Sil A
      • Rice ASC
      Systematic review of guidelines for internal validity in the design, conduct and analysis of preclinical biomedical experiments involving laboratory animals.
      With the recent publication of the ARRIVE guidelines, it is hoped that the quality of preclinical studies and their reporting will improve, thus facilitating future systematic reviews.
      • Kilkenny C
      • Browne WJ
      • Cuthill IC
      • Emerson M
      • Altman DG
      Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research.

      Conclusion

      Our results suggest that exercises, electro-acupuncture, neural mobilization, and physical agents modulate biomarkers of neuropathic pain in preclinical models.
      Only few studies were available for joint mobilization and acupuncture, thus preventing firm conclusions. Physiotherapy interventions seem to regulate the expression of a range of biomarkers particularly associated with the neuro-immune system, opioid system, neurotransmitters, neurotrophins, and receptors. The high risk of bias and poor reporting quality however prevents firm conclusions. Nevertheless, our findings may be used to inform the design of future human studies. Future preclinical studies need to follow higher standards of methodological quality and reporting to advance this promising field.

      References

        • Abbott CA
        • Malik RA
        • Van Ross ERE
        • Kulkarni J
        • Boulton AJM
        Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K.
        Diabetes Care. 2011; 34: 2220-2224
        • Ahsin S
        • Saleem S
        • Bhatti AM
        • Iles RK
        • Aslam M
        Clinical and endocrinological changes after electro-acupuncture treatment in patients with osteoarthritis of the knee.
        Pain. 2009; 147: 60-66
        • Akyuz G
        • Kenis O
        Physical therapy modalities and rehabilitation techniques in the management of neuropathic pain.
        Am J Phys Med Rehabil. 2014; 93: 253-259
        • Almeida C
        • DeMaman A
        • Kusuda R
        • Cadetti F
        • Ravanelli MI
        • Queiroz AL
        • Sousa TA
        • Zanon S
        • Silveira LR
        • Lucas G
        Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain.
        Pain. 2015; 156: 504-513
        • Andrew SCR
        • Finnerup NB.
        • Kemp HI
        • Gillian L
        Currie and RB: Sensory profiling in animal models of neuropathic pain: A call for back-translation.
        Pain. 2018; 159: 819-824
        • Austin PJ
        • Moalem-Taylor G
        The neuro-immune balance in neuropathic pain: Involvement of inflammatory immune cells, immune-like glial cells and cytokines.
        J Neuroimmunol. 2010; 229: 26-50
        • Baron R
        • Freynhagen R
        • Tölle TR
        • Cloutier C
        • Leon T
        • Murphy TK
        • Phillips K
        The efficacy and safety of pregabalin in the treatment of neuropathic pain associated with chronic lumbosacral radiculopathy.
        Pain. 2010; 150: 420-427
        • Basson A
        • Olivier B
        • Ellis R
        • Coppieters M
        • Stewart A
        • Mudzi W
        The effectiveness of neural mobilization for neuromusculoskeletal conditions: A systematic review and meta-analysis.
        J Orthop Sports Phys Ther. 2017; 47: 593-615
        • Belmonte LAO
        • Martins TC
        • Salm DC
        • Emer AA
        • de Oliveira BH
        • Mathias K
        • Goldim MP
        • Horewicz VV
        • Piovezan AP
        • Bobinski F
        • Petronilho F
        • Martins DF
        Effects of different parameters of continuous training and high-intensity interval training in the chronic phase of a mouse model of complex regional pain syndrome type I.
        J Pain. 2018; 19: 1445-1460
        • Bialosky JE
        • Bishop MD
        • Price DD
        • Robinson ME
        • George SZ
        The mechanisms of manual therapy in the treatment of musculoskeletal pain: A comprehensive model.
        Man Ther. 2009; 14: 531-538
        • Bialosky JE
        • Bishop MD
        • Price DD
        • Robinson ME
        • Vincent KR
        • George SZ
        A randomized sham-controlled trial of a neurodynamic technique in the treatment of carpal tunnel syndrome.
        J Orthop Sports Phys Ther. 2009; 39: 709-723
        • Bialosky JE
        • Bishop MD
        • Robinson ME
        • Jr GZ
        • George SZ
        Spinal manipulative therapy has an immediate effect on thermal pain sensitivity in people with low back pain: A randomized controlled trial.
        Phys Ther. 2009; 89: 1292-1303
        • Bobinski F
        • Ferreira TAA
        • Córdova MM
        • Dombrowski PA
        • da Cunha C
        • Santo CC
        • Poli A
        • Pires RGW
        • Martins-Silva C
        • Sluka KA
        • Santos ARS
        Role of brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic pain after sciatic nerve injury in mice.
        Pain. 2015; 156: 2595-2606
        • Bobinski F
        • Martins DF
        • Bratti T
        • Mazzardo-Martins L
        • Winkelmann-Duarte EC
        • Guglielmo LGA
        • Santos ARS
        Neuroprotective and neuroregenerative effects of low-intensity aerobic exercise on sciatic nerve crush injury in mice.
        Neuroscience. 2011; 194: 337-348
        • Bobinski F
        • Teixeira JM
        • Sluka KA
        • Santos ARS
        Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain.
        Pain. 2018; 159: 437-450
        • Boudier-Revéret M
        • Gilbert KK
        • Allégue DR
        • Moussadyk M
        • Brismée JM
        • Sizer PS
        • Feipel V
        • Dugailly PM
        • Sobczak S
        Effect of neurodynamic mobilization on fluid dispersion in median nerve at the level of the carpal tunnel: A cadaveric study.
        Musculoskeletal Sci Pract. 2017; 31: 45-51
      1. Cha MH, Nam TS, Kwak Y, Lee H, Lee BH: Changes in cytokine expression after electroacupuncture in neuropathic rats. Evid-based Complement Altern Med 2012.

        • Chang IA
        • Namgung U
        Induction of regenerative responses of injured sciatic nerve by pharmacopuncture therapy in rats.
        JAMS J Acupunct Meridian Stud. 2013; 6: 89-97
        • Chen X-M
        • Xu J
        • Song J-G
        • Zheng B-J
        • Wang X-R
        Electroacupuncture inhibits excessive interferon-γ evoked up-regulation of P2×4 receptor in spinal microglia in a CCI rat model for neuropathic pain.
        Br J Anaesth. 2015; 114: 150-157
        • Chen Y-W
        • Chiu C-C
        • Hsieh P-L
        • Hung C-H
        • Wang J-J
        Treadmill training combined with insulin suppresses diabetic nerve pain and cytokines in rat sciatic nerve.
        Anesth Analg. 2015; 121: 239-246
        • Chen Y-W
        • Hsieh P-L
        • Chen Y-C
        • Hung C-H
        • Cheng J-T
        Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats.
        Anesth Analg. 2013; 116: 482-490
        • Chen Y-W
        • Li Y-T
        • Chen YC
        • Li Z-Y
        • Hung C-H
        Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve.
        Anesth Analg. 2012; 114: 1330-1337
        • Chen YW
        • Tzeng JI
        • Huang PC
        • Hung CH
        • Shao DZ
        • Wang JJ
        Therapeutic ultrasound suppresses neuropathic pain and upregulation of substance p and neurokinin-1 receptor in rats after peripheral nerve injury.
        Ultrasound Med Biol. 2015; 41: 143-150
        • Ching-Hsia H
        • Po-Ching H
        • Jann-Inn T
        • Jhi-Joung W
        • Yu-Wen C
        Therapeutic ultrasound and treadmill training suppress peripheral nerve injury-induced pain in rats.
        Phys Ther Depart Phys Ther. 2016; 96: 1545-1553
        • Chunchun X
        • Lei X
        • Xia L
        • Jianfeng C
        • Zhen G
        • Kaiqiang W
        Analgesic mechanism of electroacupuncture in a rat L5 spinal nerve ligation model.
        Exp Therap Med. 2015; 9: 987-991
        • Cidral-Filho FJ
        • Martins DF
        • More AOO
        • Mazzardo-Martins L
        • Silva MD
        • Cargnin-Ferreira E
        • Santos ARS
        Light-emitting diode therapy induces analgesia and decreases spinal cord and sciatic nerve tumour necrosis factor-alpha levels after sciatic nerve crush in mice.
        Eur J Pain England;. 2013; 17: 1193-1204
        • Cioato SG
        • Medeiros LF
        • Marques Filho PR
        • Vercelino R
        • De Souza A
        • Scarabelot VL
        • De Oliveira C
        • Adachi LNS
        • Fregni F
        • Caumo W
        • Torres ILS
        Long-lasting effect of transcranial direct current stimulation in the reversal of hyperalgesia and cytokine alterations induced by the neuropathic pain model.
        Brain Stimul. 2016; 9: 209-217
        • Clark AK
        • Old EA
        • Malcangio M
        Neuropathic pain and cytokines: Current perspectives.
        J Pain Res. 2013; 6: 803-814
        • Cleland JA
        • Childs JD
        • Palmer JA
        • Eberhart S
        Slump stretching in the management of non-radicular low back pain: A pilot clinical trial.
        Man Ther. 2006; 11: 279-286
        • Cobianchi S
        • Casals-Diaz L
        • Jaramillo J
        • Navarro X
        Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury.
        Exp Neurol. 2013; 240: 157-167
        • Cobianchi S
        • Marinelli S
        • Florenzano F
        • Pavone F
        • Luvisetto S
        Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
        Neuroscience. 2010; 168: 273-287
        • Cobianchi S
        • Marinelli S
        • Florenzano F
        • Pavone F
        • Luvisetto S
        • Cobianchi S
        • Marinelli S
        • Florenzano F
        • Pavone F
        • Luvisetto S
        Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury.
        Neuroscience. 2010; 168: 273-287
        • Colloca L
        • Ludman T
        • Bouhassira D
        • Baron R
        • Dickenson AH
        • Yarnitsky D
        • Freeman R
        • Truini A
        • Attal N
        • Finnerup NB
        • Eccleston C
        • Kalso E
        • Bennett DL
        • Dworkin RH
        • Raja SN
        Neuropathic pain.
        Nat Rev Dis Primers. 2017; 3: 1-20
      2. Connor ABO, Dworkin RH: Treatment of neuropathic pain: An overview of recent guidelines 122:S22–32, 2009.

        • Coradini JG
        • Kunz RI
        • Kakihata CMM
        • Errero TK
        • Bonfleur ML
        • de Fátima Chasko Ribeiro L
        • Brancalhão RMC
        • Bertolini GRF
        Swimming does not alter nociception threshold in obese rats submitted to median nerve compression.
        Neurol Res. 2015; 37: 1118-1124
        • da Silva JT
        • Santos FM dos
        • Giardini AC
        • Martins D de O
        • de Oliveira ME
        • Ciena AP
        • Gutierrez VP
        • Watanabe IS
        • Britto LRG de
        • Chacur M
        Neural mobilization promotes nerve regeneration by nerve growth factor and myelin protein zero increased after sciatic nerve injury.
        Growth Factors. 2015; 33: 8-13
        • da Silva OR
        • Cury DP
        • Yamashita LB
        • Esteca M v
        • Watanabe I-S
        • Bergmann YF
        • Toniolo EF
        • Dale CS
        Photobiomodulation induces antinociception, recovers structural aspects and regulates mitochondrial homeostasis in peripheral nerve of diabetic mice.
        J Biophotonics. 2018; 11e201800110
        • Dong Z-Q
        • Ma F
        • Xie H
        • Wang Y-Q
        • Wu G-C
        Changes of expression of glial cell line-derived neurotrophic factor and its receptor in dorsal root ganglions and spinal dorsal horn during electroacupuncture treatment in neuropathic pain rats.
        Neurosci Lett Ireland;. 2005; 376: 143-148
        • DosSantos MF
        • Martikainen IK
        • Nascimento TD
        • Love TM
        • Deboer MD
        • Maslowski EC
        • Monteiro AA
        • Vincent MB
        • Zubieta JK
        • DaSilva AF
        Reduced basal ganglia μ-opioid receptor availability in trigeminal neuropathic pain: A pilot study.
        Mol Pain. 2012; 8: 3-8
        • Fernandez M
        • Hartvigsen J
        • Ferreira ML
        • Refshauge KM
        • Machado AF
        • Lemes ÍR
        • Maher CG
        • Ferreira PH
        Advice to stay active or structured exercise in the management of sciatica: A systematic review and meta-analysis.
        Spine (Phila Pa 1976). 2015; 40: 1457-1466
        • Fernández-De-Las Peñas C
        • Ortega-Santiago R
        • De La Llave-Rincón AI
        • Martínez-Perez A
        • Fahandezh-Saddi Díaz H
        • Martínez-Martín J
        • Pareja JA
        • Cuadrado-Pérez ML
        Manual physical therapy versus surgery for carpal tunnel syndrome: A randomized parallel-group trial.
        J Pain. 2015; 16: 1087-1094
        • Filho PRM
        • Vercelino R
        • Cioato SG
        • Medeiros LF
        • de Oliveira C
        • Scarabelot VL
        • Souza A
        • Rozisky JR
        • Quevedo A da S
        • Adachi LNS
        • Sanches PRS
        • Fregni F
        • Caumo W
        • Torres ILS
        Transcranial direct current stimulation (tDCS) reverts behavioral alterations and brainstem BDNF level increase induced by neuropathic pain model: Long-lasting effect.
        Prog Neuro-Psychopharmacol Biol Psychiatry. 2016; 64: 44-51
        • Finnerup NB
        • Haroutounian S
        • Baron R
        • Dworkin RH
        • Gilron I
        • Haanpaa M
        • Jensen TS
        • Kamerman PR
        • Mcnicol E
        • Moore A
        • Raja SN
        • Andersen NT
        • Sena ES
        • Smith BH
        • Rice ASC
        Neuropathic pain clinical trials: factors associated with decreases in estimated drug efficacy.
        Pain. 2018; 159: 2339-2346
        • Finnerup NB
        • Sindrup SH
        • Jensen TS
        The evidence for pharmacological treatment of neuropathic pain.
        Pain Int Assoc Study Pain. 2010; 150: 573-581
        • Furlan AD
        • Pennick V
        • Bombardier C
        • van Tulder M
        2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group.
        Spine (Phila Pa 1976). 2009; 34: 1929-1941
        • Galantino MLA
        • Eke-Okoro ST
        • Findley TW
        • Condoluci D
        Use of noninvasive electroacupuncture for the treatment of HIV-related peripheral neuropathy: A pilot study.
        J Altern Complement Med. 1999; 5: 135-142
        • Gao Y-H
        • Wang J-Y
        • Qiao L-N
        • Chen S-P
        • Tan L-H
        • Xu Q-L
        • Liu J-L
        NK cells mediate the cumulative analgesic effect of electroacupuncture in a rat model of neuropathic pain.
        BMC Complement Altern Med. 2014; 14: 316
        • Giardini AC
        • Santos FM
        • Dos Da
        • Silva JT
        • De Oliveira ME
        • Martins DO
        • Chacur M
        Neural mobilization treatment decreases glial cells and brain-derived neurotrophic factor expression in the central nervous system in rats with neuropathic pain induced by CCI in rats.
        Pain Res Manag. 2017;
        • Gibson W
        • Wand BM
        • O'Connell NE
        Transcutaneous electrical nerve stimulation (TENS) for neuropathic pain in adults.
        Cochrane Database Syst Rev. 2017; 2017
        • Gilron I
        • Bailey JM
        • Tu D
        • Holden RR
        • Weaver DF
        • Houlden RL
        Morphine, gabapentin, or their combination for neuropathic pain.
        N Engl J Med. 2005; 352: 1324-1334
        • Giuliani A
        • Fernandez M
        • Farinelli M
        • Baratto L
        • Capra R
        • Rovetta G
        • Monteforte P
        • Giardino L
        • Calzà L
        Very low level laser therapy attenuates edema and pain in experimental models.
        Int J Tissue React. 2004; 26: 29-37
        • Gong X
        • Chen Y
        • Fu B
        • Jiang J
        • Zhang M
        Infant nerve injury induces delayed microglial polarization to the M1 phenotype, and exercise reduces delayed neuropathic pain by modulating microglial activity.
        Neuroscience. 2017; 349: 76-86
        • Guo JB
        • Chen BL
        • Wang Y
        • Zhu Y
        • Song G
        • Yang Z
        • Zheng YL
        • Wang XQ
        • Chen PJ
        Meta-analysis of the effect of exercise on neuropathic pain induced by peripheral nerve injury in rat models.
        Front Neurol. 2019; 10: 1-12
        • Haanpää M
        • Attal N
        • Backonja M
        • Baron R
        • Bennett M
        • Bouhassira D
        • Cruccu G
        • Hansson P
        • Haythornthwaite JA
        • Iannetti GD
        • Jensen TS
        • Kauppila T
        • Nurmikko TJ
        • Rice ASC
        • Rowbotham M
        • Serra J
        • Sommer C
        • Smith BH
        • Treede RD
        NeuPSIG guidelines on neuropathic pain assessment.
        Pain Int Assoc Study Pain. 2011; 152: 14-27
        • Han J-S
        Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies.
        Trends Neurosci. 2003; 26: 17-21
        • Held M
        • Karl F
        • Vlckova E
        • Rajdova A
        • Escolano-Lozano F
        • Stetter C
        • Bharti R
        • Förstner KU
        • Leinders M
        • Dušek L
        • Birklein F
        • Bednarik J
        • Sommer C
        • Üçeyler N
        Sensory profiles and immune-related expression patterns of patients with and without neuropathic pain after peripheral nerve lesion.
        Pain. 2019; 160: 2316-2327
        • Herzberg U
        • Eliav E
        • Dorsey JM
        • Gracely RH
        • Kopin IJ
        NGF involvement in pain induced by chronic constriction injury of the rat sciatic nerve.
        Neuroreport. 1997; 8: 1613-1618
        • Higgins JPT
        GST a cargo del CCI: Manual Cochrane de revisiones sistemáticas de intervenciones.
        Man Cochrane. 2011; 510
        • Hooijmans CR
        • Rovers MM
        • De Vries RBM
        • Leenaars M
        • Ritskes-Hoitinga M
        • Langendam MW
        SYRCLE's risk of bias tool for animal studies.
        BMC Med Res Methodol. 2014; 14: 1-9
        • Hsieh YL
        • Chen HY
        • Yang CH
        • Yang CC
        Analgesic effects of transcutaneous ultrasound nerve stimulation in a rat model of oxaliplatin-induced mechanical hyperalgesia and cold allodynia.
        Ultrasound Med Biol. 2017; 43: 1466-1475
        • Hsieh Y-L
        • Chou L-W
        • Chang P-L
        • Yang C-C
        • Kao M-J
        • Hong C-Z
        Low-level laser therapy alleviates neuropathic pain and promotes function recovery in rats with chronic constriction injury: possible involvements in hypoxia-inducible factor 1alpha (HIF-1alpha).
        J Comp Neurol. 2012; 520: 2903-2916
        • Huang PC
        • Tsai KL
        • Chen YW
        • Lin HT
        • Hung CH
        Exercise combined with ultrasound attenuates neuropathic pain in rats associated with downregulation of IL-6 and TNF-α, but with upregulation of IL-10.
        Anesth Analg. 2017; 124: 2038-2044
        • Hubertus Köller M.D.
        • Bernd C.
        • Kieseier M.D.
        • Sebastian Jander MD
        • Hans-Peter Hartung MD
        Chronic inflammatory demyelinating polyneuropathy.
        Adv Exp Med Biol. 2019; 1190: 333-343
        • Hui ACF
        • Wong SM
        • Leung HW
        • Man BL
        • Yu E
        • Wong LKS
        Gabapentin for the treatment of carpal tunnel syndrome: A randomized controlled trial.
        Eur J Neurol. 2011; 18: 726-730
        • Jensen TS
        • Madsen CS
        • Finnerup NB
        Pharmacology and treatment of neuropathic pains.
        Curr Opin Neurol. 2009; 22: 467-474
        • Jeremy Howick
        • Chalmers Iain
        • Glasziou Paul
        • Greenhalg Trsh
        • Heneghan Carl
        • Liberti Alessandro
        • Ivan Moschetti BP
        • HT
        The 2011 Oxford CEBM Levels of Evidence (introductory Document).
        Oxford Center for Evidence-Based Medicine, 2011
        • Jesson T
        • Runge N
        • Schmid AB
        Physiotherapy for people with painful peripheral neuropathies: A narrative review of its efficacy and safety.
        Pain Rep. 2020; 5: 1-e834
        • Ju ZY
        • Wang K
        • Cui HS
        • Yao Y
        • Liu SM
        • Zhou J
        • Chen TY
        • Xia J
        Acupuncture for neuropathic pain in adults.
        Cochrane Database Syst Rev. 2017; 2017
        • Kami K
        • Taguchi S
        • Tajima F
        • Senba E
        Histone acetylation in microglia contributes to exercise-induced hypoalgesia in neuropathic pain model mice.
        Pain. 2016; 17: 588-599
        • Kami K
        • Tajima F
        • Senba E
        Activation of cyclic AMP response element-binging protein in dopaminergic neurons in the ventral tegmental area via voluntary wheel running contributes to exercise-induced hypoalgesia in a mouse model of neuropathic pain.
        Pain Res. 2016; 31: 238-251
        • Kanzawa-Lee GA
        • Larson JL
        • Resnicow K
        • Smith EML
        Exercise effects on chemotherapy-induced peripheral neuropathy: A comprehensive integrative review.
        Cancer Nurs. 2020; 43: 172-185
        • Kilkenny C
        • Browne WJ
        • Cuthill IC
        • Emerson M
        • Altman DG
        Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research.
        PLOS Biol Public Libr Sci. 2010; 8e1000412
        • Korb A
        • Bonetti L V
        • Da Silva SA
        • Marcuzzo S
        • Ilha J
        • Bertagnolli M
        • Partata WA
        • Faccioni-Heuser MC
        Effect of treadmill exercise on serotonin immunoreactivity in medullary raphe nuclei and spinal cord following sciatic nerve transection in rats.
        Neurochem Res. 2010; 35: 380-389
        • Krouwel O
        • Hebron C
        • Willett E
        An investigation into the potential hypoalgesic effects of different amplitudes of PA mobilisations on the lumbar spine as measured by pressure pain thresholds (PPT).
        Man Ther. 2010; 15: 7-12
        • Leenaars M
        • Hooijmans CR
        • van Veggel N
        • ter Riet G
        • Leeflang M
        • Hooft L
        • van der Wilt GJ
        • Tillema A
        • Ritskes-Hoitinga M
        A step-by-step guide to systematically identify all relevant animal studies.
        Lab Anim;. 2012; 46: 24-31
        • Li Y
        • Yin C
        • Li X
        • Liu B
        • Wang J
        • Zheng X
        • Shao X
        • Liang Y
        • Du J
        • Fang J
        • Liu B
        Electroacupuncture alleviates paclitaxel-induced peripheral neuropathic pain in rats via suppressing TLR4 signaling and TRPV1 upregulation in sensory neurons.
        Int J Mol Sci. 2019; 20
        • Liang Y
        • Du J-Y
        • Qiu Y-J
        • Fang J-F
        • Liu J
        • Fang J-Q
        Electroacupuncture attenuates spinal nerve ligation-induced microglial activation mediated by p38 mitogen-activated protein kinase.
        Chin J Integr Med. 2016; 22: 704-713
        • Liang Y
        • Qiu Y
        • Du J
        • Liu J
        • Fang J
        • Zhu J
        • Fang J
        Inhibition of spinal microglia and astrocytes contributes to the anti-allodynic effect of electroacupuncture in neuropathic pain induced by spinal nerve ligation.
        Acupunct Med. 2016; 34: 40-47
        • Lin H-T
        • Chiu C-C
        • Wang J-J
        • Hung C-H
        • Chen Y-W
        High frequency transcutaneous electrical nerve stimulation with diphenidol administration results in an additive antiallodynic effect in rats following chronic constriction injury.
        Neurosci Lett. 2015; 589: 62-66
        • Liu H
        • Ma Y
        • Liu J
        • Guo Z
        • Yan W
        • Wen S
        • Zhao Q
        • Guo X
        • Zhang X
        • Sheng Q
        Therapeutic effect of electroacupuncture on rats with neuropathic pain.
        Int J Clin Exp Med. 2019; 12: 8531-8539
        • Lopez-Alvarez VM
        • Modol L
        • Navarro X
        • Cobianchi S
        Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury.
        Pain. 2015; 156: 1812-1825
        • Lopez-Alvarez VM
        • Puigdomenech M
        • Navarro X
        • Cobianchi S
        Monoaminergic descending pathways contribute to modulation of neuropathic pain by increasing-intensity treadmill exercise after peripheral nerve injury.
        Exp Neurol. 2018; 299: 42-55
        • Macleod MR
        • Fisher M
        • O'Collins V
        • Sena ES
        • Dirnagl U
        • Bath PMW
        • Buchan A
        • van der Worp HB
        • Traystman R
        • Minematsu K
        • Donnan GA
        • Howells DW
        Good laboratory practice: preventing introduction of bias at the bench.
        Stroke. 2009; 40: 50-52
        • Madsen MV
        • Gøtzsche PC
        • Hróbjartsson A
        Acupuncture treatment for pain: Systematic review of randomised clinical trials with acupuncture, placebo acupuncture, and no acupuncture groups.
        BMJ (Online). 2009; 338: 330-333
        • Manni L
        • Florenzano F
        • Aloe L
        Electroacupuncture counteracts the development of thermal hyperalgesia and the alteration of nerve growth factor and sensory neuromodulators induced by streptozotocin in adult rats.
        Diabetologia Germany. 2011; 54: 1900-1908
        • Martins DF
        • Mazzardo-Martins L
        • Gadotti VM
        • Nascimento FP
        • Lima DAN
        • Speckhann B
        • Favretto GA
        • Bobinski F
        • Cargnin-Ferreira E
        • Bressan E
        • Dutra RC
        • Calixto JB
        • Santos ARS
        Ankle joint mobilization reduces axonotmesis-induced neuropathic pain and glial activation in the spinal cord and enhances nerve regeneration in rats.
        Pain. 2011; 152: 2653-2661
        • Matsuo H
        • Uchida K
        • Nakajima H
        • Guerrero AR
        • Watanabe S
        • Takeura N
        • Sugita D
        • Shimada S
        • Nakatsuka T
        • Baba H
        Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.
        Pain Int Assoc Study Pain;. 2014; 155: 1888-1901
        • Mert T
        • Altun I
        • Celik A
        • Surer T
        • Gunay I
        Modulation of cytokine levels in ameliorative effects of pulsed magnetic field on an experimental model of Chronic Constriction Injury.
        Int J Radiat Biol England;. 2015; 91: 596-602
        • Mert T
        • Gisi G
        • Celik A
        • Baran F
        • Uremis MM
        • Gunay I
        Frequency-dependent effects of sequenced pulsed magnetic field on experimental diabetic neuropathy.
        Int J Radiat Biol England;. 2015; 91: 833-842
        • Moss P
        • Sluka K
        • Wright A
        The initial effects of knee joint mobilization on osteoarthritic hyperalgesia.
        Man Ther. 2007; 12: 109-118
        • National Institute for Health and Care Excellence
        Low back pain and sciatica in over 16s: assessment and management (NG59).
        Nice. 2016; : 1-18
        • Naugle KM
        • Naugle KE
        • Fillingim RB
        • Samuels B
        • Riley JL
        Intensity thresholds for aerobic exercise-induced hypoalgesia.
        Med Sci Sports Exerc. 2014; 46: 817-825
        • Nori SL
        • Rocco ML
        • Florenzano F
        • Ciotti MT
        • Aloe L
        • Manni L
        Increased nerve growth factor signaling in sensory neurons of early diabetic rats is corrected by electroacupuncture.
        Evid-Based Complement Altern Med. 2013;
        • O´connor AlecB
        Neuropathic pain quality of life impact, costs and const effectivenes of Therapy.
        Pharmacoeconomics. 2009; 27: 95-1112
        • O'Connor AB
        Neuropathic pain.
        Pharmacoeconomics. 2012; 27: 95-112
        • O'Connor AB
        • Dworkin RH
        Treatment of neuropathic pain: An overview of recent guidelines.
        Am J Med. 2009; 122: S22-S32
        • Page MJ
        • McKenzie JE
        • Bossuyt PM
        • Boutron I
        • Hoffmann TC
        • Mulrow CD
        • Shamseer L
        • Tetzlaff JM MD
        Updating guidance for reporting systematic reviews: development of the PRISMA 2020 statement.
        J Clin Epidemiol. 2021; : 1-22
        • Penza P
        • Bricchi M
        • Scola A
        • Campanella A
        • Lauria G
        Electroacupuncture is not effective in chronic painful neuropathies.
        Pain Medicine. 2011; 12: 1819-1823
        • Percie Du Sert N
        • Rice ASC
        Improving the translation of analgesic drugs to the clinic: Animal models of neuropathic pain.
        Br J Pharmacol. 2014; 171: 2951-2963
        • Polaski AM
        • Phelps AL
        • Kostek MC
        • Szucs KA
        • Kolber BJ
        Exercise-induced hypoalgesia: A meta-analysis of exercise dosing for the treatment of chronic pain.
        PLoS One. 2019; 14: 1-29
        • Porreca F
        • Tang QB
        • Bian D
        • Riedl M
        • Eide R
        • Lai J
        Spinal opioid mu receptor expression in lumbar spinal cord of rats following nerve injury.
        Brain Res. 1998; 795: 197-203
        • Rosen S
        • Ham B
        • Mogil JS
        Sex differences in neuroimmunity and pain.
        J Neurosci Res. 2017; 95: 500-508
        • Santos FM
        • Silva JT
        • Giardini AC
        • Rocha PA
        • Achermann AP
        • Alves AS
        • Britto LR
        • Chacur M
        Neural mobilization reverses behavioral and cellular changes that characterize neuropathic pain in rats.
        Mol Pain. 2012; 8 (1744-8069-8–57)
        • Santos FM
        • Silva JT
        • Rocha IRC
        • Martins DO
        • Chacur M
        Non-pharmacological treatment affects neuropeptide expression in neuropathic pain model.
        Brain Res Elsevier B.V. 2018; 1687: 60-65
        • Schmid A
        • Brunner F
        • Wright A
        • Bachmann LM
        Paradigm shift in manual therapy? Evidence for a central nervous system component in the response to passive cervical joint mobilisation.
        Man Ther. 2008; 13: 387-396
        • Schmid AB
        • Elliott JM
        • Strudwick MW
        • Little M
        • Coppieters MW
        Effect of splinting and exercise on intraneural edema of the median nerve in carpal tunnel syndrome-an MRI study to reveal therapeutic mechanisms.
        J Orthop Res. 2012; 30: 1343-1350
        • Scholz J
        • Woolf CJ
        The neuropathic pain triad: Neurons, immune cells and glia.
        Nat Neurosci. 2007; 10: 1361-1368
        • Seifert F
        • Kiefer G
        • Decol R
        • Schmelz M
        • Maihöfner C
        Differential endogenous pain modulation in complex-regional pain syndrome.
        Brain. 2009; 132: 788-800
        • Siniscalco D
        • Giordano C
        • Rossi F
        • Maione S
        • de Novellis V
        Role of neurotrophins in neuropathic pain.
        Curr Neuropharmacol. 2011; 9: 523-529
        • Smith BH
        • Hébert HL
        • Veluchamy A
        Neuropathic pain in the community: prevalence, impact, and risk factors.
        Pain. 2020; 161: S127-S137
        • Somers DL
        • Clemente FR
        Contralateral high or a combination of high- and low-frequency transcutaneous electrical nerve stimulation reduces mechanical allodynia and alters dorsal horn neurotransmitter content in neuropathic rats.
        J Pain. 2009; 10: 221-229
        • Sommer C
        • Leinders M
        • Üçeyler N
        Inflammation in the pathophysiology of neuropathic pain.
        Pain. 2018; 159: 595-602
        • Song SJ
        • Min J
        • Suh SY
        • Jung SH
        • Hahn HJ
        • Im SA
        • Lee JY
        Incidence of taxane-induced peripheral neuropathy receiving treatment and prescription patterns in patients with breast cancer.
        Supportive Care Cancer. 2017; 25: 2241-2248
        • Song XJ
        • Huang ZJ
        • Song WB
        • Song XS
        • Fuhr AF
        • Rosner AL
        • Ndtan H
        • Rupert RL
        Attenuation effect of spinal manipulation on neuropathic and postoperative pain through activating endogenous anti-inflammatory cytokine interleukin 10 in rat spinal cord.
        J Manipulative Physiol Ther. 2016; 39: 42-53
        • Soon B
        • Vicenzino B
        • Schmid AB
        • Coppieters MW
        Facilitatory and inhibitory pain mechanisms are altered in patients with carpal tunnel syndrome.
        PLOS One. 2017;
        • Su H-L
        • Chiang C-Y
        • Lu Z-H
        • Cheng F-C
        • Chen C-J
        • Sheu M-L
        • Sheehan J
        • Pan H-C
        Late administration of high-frequency electrical stimulation increases nerve regeneration without aggravating neuropathic pain in a nerve crush injury.
        BMC Neurosci Pan. 2018; 19
        • Sumizono M
        • Sakakima H
        • Otsuka S
        • Terashi T
        • Nakanishi K
        • Ueda K
        • Takada S
        • Kikuchi K
        The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model.
        J Pain Res. 2018; 11: 281-291