Cover Art Gallery
Adverse life events (ALEs) are a risk factor for chronic pain; however, mechanisms underlying this association are not understood. This study examined whether cumulative ALE exposure impairs endogenous inhibition of pain (assessed from pain report) and spinal nociception (assessed from nociceptive flexion reflex; NFR) in healthy, pain-free Native Americans (n = 124) and non-Hispanic Whites (n = 129) during a conditioned pain modulation (CPM) task. Cumulative ALE exposure was assessed prior to testing by summing the number of potentially traumatic events experienced by each participant across their lifespan. Multilevel modeling found that ALEs were associated with NFR modulation during the CPM task even after controlling for general health, body mass index, sex, age, blood pressure, sleep quality, stimulation intensity, stimulus number, perceived stress, and psychological distress. Low exposure to ALEs was associated with NFR inhibition, whereas high exposure to ALEs was associated with NFR facilitation. By contrast, pain perception was inhibited during the CPM task regardless of the level of ALE exposure. Race/ethnicity did not moderate these results. Thus, ALEs may be pronociceptive for both Native Americans and non-Hispanic Whites by impairing descending inhibition of spinal nociception. This could contribute to a chronic pain risk phenotype involving latent spinal sensitization. See Kell, et al, Page 1097.
Adverse life events (ALEs) are a risk factor for chronic pain; however, mechanisms underlying this association are not understood. This study examined whether cumulative ALE exposure impairs endogenous inhibition of pain (assessed from pain report) and spinal nociception (assessed from nociceptive flexion reflex; NFR) in healthy, pain-free Native Americans (n = 124) and non-Hispanic Whites (n = 129) during a conditioned pain modulation (CPM) task. Cumulative ALE exposure was assessed prior to testing by summing the number of potentially traumatic events experienced by each participant across their lifespan. See Kell, et al, Page 1097.
Chemotherapy-Induced Peripheral Neuropathy is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, the authors evaluated the effect of three antioxidants - namely Nacetylcysteine, α-lipoic acid and vitamin E - upon nociceptive parameters and antitumor efficacy of OXA in a tumor bearing Swiss mice model. The results report preventive and therapeutic efficacy of orally administrated antioxidants (Nacetylcysteine, α-lipoic-acid and Vitamin-E) for alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds. See Agnes, et al, Page 996.
A growing body of evidence supports the modulation of pain by light exposure. As such, phototherapy is increasingly utilized for the management of pain conditions. The modes of delivery and applications of phototherapy vary by wavelength, intensity, and route of exposure. Differing mechanisms of action exist depending upon those parameters. This review article synopsizes the pathways and mechanisms through which light modulates pain and the therapeutic utility of different colors and exposure modalities of light on pain. Recent advances in photobiomodulation provide a foundation for understanding this novel treatment for pain on which future translational and clinical studies can build upon. See Cheng et al, page 763.
The protease activated receptor (PAR) family is a group of G-protein coupled receptors activated by proteolytic cleavage of the extracellular domain. PARs are expressed in a variety of cell types with crucial roles in hemostasis, immune responses, inflammation, and pain. PAR3 is the least researched of the four PARs. This work aimed to better understand its potential function in the peripheral sensory nervous system by evaluating the role of PAR3, a G-protein coupled receptor, in nociception by developing a selective peptide agonist. These results suggest that PAR3 contributes to nociception in various contexts and plays a role in modulating the activity of other PARs. See Mwirigi, et al, Page 692.
A significant breakthrough in the field of somatosensation was the discovery of a second tactile system in humans. Yet the possible pain-relieving effect of affective touch (AT) have been poorly investigated. This report demonstrates that AT can decrease pain in a lab-based clinically-relevant human model. This work extends findings on the analgesic potential of AT, documenting a clear pain reduction during temporal summation of second pain. Targeting C-tactile fibers responsible for AT could help discover new treatments for chronic pain conditions, the authors conclude. See Fidanza, et al, Page 567.
Effective treatment of neuropathic pain is lacking, largely due to an incomplete understanding of the pathogenesis. In this study, three main experiments were designed to investigate the mechanism of anti-nociception induced by intrathecally administrated endothelin-1 in neuropathic pain. Findings show that inducing spinal GABAergic neuronal HDAC5 nuclear exportation may be a novel therapeutic approach for managing neuropathic pain. Characterizing the anti-nociceptive effect of ET-1 and investigating the associated epigenetic mechanisms in animal models may lead to the development of new therapeutic strategies and targets for treating neuropathic pain, the authors conclude. See Gu, et al, Page 454.
Oxylipins are lipid peroxidation products that participate in nociceptive, inflammatory, and vascular responses to injury. Effects of oxylipins depend on tissue-specific differences in accumulation of precursor polyunsaturated fatty acids, and the expression of specific enzymes to transform the precursors. There has been a knowledge gap in the way these molecules operate in nociception. This study applied a systems-based approach to characterize oxylipin precursor fatty acids, and expression of genes coding for proteins involved in biosynthesis, transport, signaling and inactivation of pro- and antinociceptive oxylipins in pain circuit tissues. The findings reported here advance the understanding of molecular lipidomic systems linking oxylipins and their precursors to nociceptive and inflammatory signaling pathways in rats. See Domenichiello, et al, Page 275.
The management of persistent postsurgical pain and neuropathic pain remains a challenge. Local anesthetics have been widely used as simple and effective treatment for these disorders, but the duration of their effect is short. This study reports on a new poly lactic-co-glycolic acid (PLGA)-coated ropivacaine that was continuously released in vitro for at least six days. This injectable PLGAcoated ropivacaine represents a new and highly promising avenue in the management of postsurgical pain and neuropathic pain, the authors conclude. See Tian, et al, Page 180.
Orofacial pain is characterized by its easy spread to adjacent areas, thus presenting with primary hyperalgesia (hypersensitivity at the site of injury) and secondary hyperalgesia (extra-territorial hypersensitivity outside the injured zone). The mechanisms behind the secondary hyperalgesia are poorly understood. In this study, the authors used a mouse model of partial transection of the infraorbital nerve (pT-ION) to study whether calcium channel subunit a2d1 (Cava2d1) and its downstream signaling contributes to the development of secondary hyperalgesia in the orofacial area. See Chu, et al, Page 238.
This study sought to investigate the underlying mechanisms via which with-nolysine kinases 1 (WNK1) contributed to bone cancer pain (BCP). A rat model of BCP was induced by Walker-256 tumor cell implantation. WNK1 expression and distribution in the lumbar spinal cord dorsal horn and dorsal root ganglion were examined. Findings demonstrate that the WNK1-SPAK/OSR1 signaling contributed to BCP in rats via regulating NKCC1 and KCC2. Suppressing this pathway reduced pain behaviors. Based on these findings, the WNK1-SPAK/OSR1 signaling may be a potential target for BCP therapy. See Gao, et al, Page 1416.
Type 1 diabetes is often associated with many co-morbid complications. Diabetic peripheral neuropathy (DPN) stands out to be one of the most common. Wnt signaling pathway has been investigated extensively for its diverse metabolic and pain modulating mechanisms and recently, its involvement has been postulated in the development of neuropathic pain. Blockade of this pathway using Wnt inhibitors provided neuroprotection in experimental DPN in rats. This study emphasizes the involvement of Wnt signalling pathway in diabetic peripheral neuropathy (DPN). This study may provide a basis for exploring the therapeutic potential of Wnt inhibitors in DPN patients. See Resham and Sharma, Page 1338.
It has been recommended that the morphine milligram equivalent dose in patients receiving opioid therapy be lowered in order to reduce opioid-related overdose and death. There are limited pharmacologic options for patients seeking an alternative to schedule II opioids who still require effective analgesia. A critical challenge therefore exists to identify safer analgesic options that reduce the risk of treatment related death. The authors indicate that this is the first study of desmetramadol in humans and the first to show it provides the same safety and analgesia as tramadol, but without tramadol’s metabolic liabilities and related drug-drug interactions. Desmetramadol could potentially offer expanded safety and utility to clinicians seeking an alternative to schedule II opioids. See Zebala, et al, Page 1218.
This cover image is provided courtesy of Kathleen Sluka. The image, “Neuroimmune Interactions,” is a painting of neurons with their dendrites intermingling. Interspersed between the neurons are microglia cells. Microglia cells support the neurons and become activated to make neurons more excitable during acute and chronic pain. Sluka is a Journal of Pain Editorial Board member and professor of Physical Therapy and Rehabilitation Science at the University of Iowa, where she studies peripheral and central mechanisms of chronic musculoskeletal pain as well as non-pharmacological treatment for chronic pain. Additional artwork can be viewed at www.kathleenslukaart.com.
Adverse life experiences (ALEs) are associated with hyperalgesia and chronic pain, but the underlying mechanisms are poorly understood. One potential mechanism is hyperexcitability of spinal neurons. Given that Native Americans (NA) are more likely to have ALEs, and have a higher prevalence of chronic pain, the relationship between ALEs and spinal hyperexcitability might contribute to their pain risk. This research assessed temporal summation of the nociceptive flexion reflex and pain in 246 healthy, pain-free non-Hispanic whites and NAs. This study found a dose-dependent relationship between ALEs and spinal neuron excitability. Although the relationship was not stronger in NAs than non-Hispanic whites, given prior evidence that NAs experience more ALEs, this could contribute to the higher prevalence of chronic pain in NAs. See Sturycz et al, page 941.
Sickle cell disease (SCD) is a group of inherited hemoglobinopathies that form sickle-shaped erythrocytes. Affected individuals, who are predominantly of African descent, experience acute episodes of pain. Acute pain episodes are the most common complication in patients with SCD. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the US Food and Drug Administration and the American Pain Society have collaborated to create a multidimensional taxonomy for acute pain, with one such effort focused on SCD. See Field, et al, page 746.
Mindfulness-based training reduces pain in clinical and experimental settings. Evidence suggests that these beneficial effects are facilitated via an increased focus on the present moment and a reduced emotional enhancement of pain. The authors measured trait mindfulness and pain responsivity in 40 healthy volunteers naive to mindfulness meditation. Consistent with trained-mindfulness studies, results show that mindfulness is associated with variations in neural connectivity linked to sensory and evaluative processes. See Salomons, et al, Page 645.
Paclitaxel-induced peripheral neuropathy (PIPN) and associated neuropathic pain are the most common and serious adverse effects experienced by cancer patients receiving paclitaxel treatment. These effects adversely impact daily activities and consequently the quality of life, sometimes forcing the suspension of treatment. The results of this study conclude that retigabine (a clinically available medicine) can be used to attenuate the development of paclitaxel-induced peripheral neuropathy, as shown by both morphologic and behavioral evidence. See See Li, et al, page 528.
In experiments on pain, participants are frequently exposed to non-painful and painful stimuli, yet the conventional pain-rating scales lack a nonpainful range and a clear point of transition from non-painful to painful events. The Sensation and Pain Rating Scale (SPARS) assesses the full stimulus intensity range, extending from no sensation (rating: - 50) to worst pain imaginable (rating: +50), and it explicitly identifies pain threshold (rating: 0). In this study, the authors tested the SPARS in two experiments using laser heat stimuli to establish its stimulus-response characteristics, and to compare it to scales that assess non-painful and painful events. These findings may be useful to research that involves exposing participants to a range of stimulation intensities or requires a clear distinction between non-painful and painful events. See Madden, et al, page 472.
Chronic pain is associated with maladaptive reorganization of the central nervous system. Studies have suggested that disorganization of large-scale electrical brain activity patterns plays a key role in the pathophysiology of chronic pain. Yet, little is known about whether and how such network pathologies can be targeted with noninvasive brain stimulation as a nonpharmacological treatment option. The authors report that transcranial alternative current stimulation could be a treatment approach for patients with chronic lower back pain. See Ahn, et al, page 277.
The multidimensional nature of chronic pain is not reflected by definitions based solely on pain duration, resulting in high prevalence estimates limiting effective policy development. The newly proposed concept of High Impact Chronic Pain (HICP) incorporates both disability and pain duration to identify a more severely impacted portion of the chronic pain population, yet remains uncharacterized at the population level. This research concludes that HICP differentiates those with debilitating chronic pain from those with less impactful chronic pain. This classification will improve clinical practice, research and the development of effective health policy. See Pitcher et al, page 146.
Acupoint catgut embedding (ACE) is a widely used traditional Chinese medicine method to manage various diseases, including chronic inflammatory pain. The authors sought to assess the possible analgesic effects of ACE in comparison to electroacupuncture (EA) and to study the analgesic mechanisms of ACE in a rat model of inflammatory pain, induced by injection of complete Freund’s adjuvant (CFA) into the hind paw of rats. This work may help the clinicians to verify the effectiveness of ACE analgesia and to better understand the underlying mechanism. See Cui et al, page 16.
Chronic overlapping pain conditions (COPCs) remain ineffectively managed by conventional pharmacotherapies. Here, the authors demonstrate that acupuncture alleviates persistent pain and neuroinflammation linked to heightened catecholaminergic tone. Mice with superior healing capacity exhibit greater analgesic efficacy. Findings indicate acupuncture as an effective treatment for COPCs and provide insight into treatment response variability. See Kim et al, page 1384.e1.
Neuropathic pain (NP) of central origin is one of the most debilitating secondary consequences of spinal cord injury (SCI). It is widely believed that cortical changes are a consequence of long-standing NP. In this paper, the authors demonstrate that NP in people with subacute SCI has characteristic electroencephalographic (EEG) markers which precede the onset of pain. The EEG reactivity to opening eyes was reduced in the alpha band and absent in the theta and beta bands in participants who later developed pain, and it was reduced in participants who already had pain, this study shows. See Vuckovic, et al, page 11256.e1.
Distal limb fracture is the most common cause of complex regional pain syndrome (CRPS), thus the rodent tibia fracture model (TFM) was developed to study CRPS pathogenesis. This comprehensive review summarizes the published TFM research and compares these experimental results with the CRPS literature. Multiple neuroimmune signaling mechanisms contribute to the pain, inflammation, and trophic changes observed in the injured limb of the rodent TFM. This model replicates many of the symptoms, signs, and pathophysiology of early CRPS, but most post fracture changes resolve within 5 months and may not contribute to perpetuating chronic CRPS, the authors report. See See Kingery et al, page 1102.e1.
The field of human pain neuroimaging has exploded in the last two decades. During this time, the broader neuroimaging community has continued to investigate and refine methods. Another key to progress is exchange with clinicians and pain scientists working with other model systems and approaches. These collaborative efforts require that non-imagers be able to evaluate and assess the evidence provided in these papers. In this article, the authors provide a guideline for designing, reading, evaluating, analyzing, and reporting results of a pain neuroimaging experiment, with a focus on functional and structural magnetic resonance imagine. This image portrays the convolution of a block design study. See Moayedi et al, page 961.
Generalized hyperalgesia and impaired pain modulation are reported in chronic low back pain (LBP). Few studies have tested whether these features are present in the acute phase. This study aimed to test for differences in pain presentation in early-acute LBP and evaluate the potential contribution of other factors to variation in sensitivity. The image shown portrays hierarchical clustering of patients based on principal component analysis, displayed as a heatmap and dendogram in which the principal component scores are represented by shades of red (positive) and blue (negative). See Klyne et al, page 942.
Pain after spinal cord injury (SCI-Pain) is often characterized as relentless, excruciating pain that is largely refractory to treatments. While it is generally agreed that SCI-Pain results from maladaptive plasticity in the pain processing pathway that includes the spinothalamic tract and somatosensory thalamus, the specific mechanisms underlying the development and maintenance of such pain are yet unclear. This research discusses mechanisms that may influence SCI-Pain. See Park et al, page 727.
Conditioned pain modulation (CPM), a psychophysical paradigm that is commonly used to infer the integrity of endogenous pain-altering systems by observation of the effect of one noxious stimulus on another, has previously identified deficient endogenous analgesia in fibromyalgia (FM) and other chronic pain conditions. The mechanisms underlying this deficiency, be they insufficient inhibition and/or active facilitation, are largely unknown. This cross-sectional study used a combination of behavioral CPM testing, voxel-based morphometry, and resting state functional connectivity to identify neural correlates of CPM in healthy controls and FM patients. Harper et al, article description on page 635.
Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, including brain regions involved in sensory processing and modulation of pain. This research sought to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared to healthy controls and a disease control group (irritable bowel syndrome). Alterations in microstructure in provoked vestibulodynia were observed in fibers associated with sensorimotor integration and pain processing. These alterations may contribute to increased pain sensitivity and tenderness, the authors report. See Gupta et al, article description on page 528.
Complex Regional Pain Syndrome (CRPS) is an unexplained chronic, debilitating pain condition that is characterized by disproportionate pain, swelling, vasomotor, sudomotor, trophic and motor changes. Observations of tactile misperceptions in patients with CRPS have prompted investigation of somatosensory neuroplasticity as a putative mechanism in CRPS pain. In a case-control design, the authors compared middle and late-latency somatosensory-evoked potentials in response to pseudorandomized mechanical stimulation of the digits of both hands (including CRPS-affected and non-affected sides) between 13 CRPS patients and 13 matched healthy controls. See Kuttikat et al, page 395.
In conjunction with the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration and the American Pain Society (APS), the ACTTION-APS Pain Taxonomy (AAPT) initiative strove to develop the characteristics of a diagnostic system useful for clinical and research purposes across disciplines and types of chronic pain conditions. Here, the authors present the proposed AAPT criteria for irritable bowel syndrome, the most common chronic, non-cancer abdominal pain condition. The AAPT’s goal is to develop an evidence-based taxonomy for chronic pain based on a consistently applied multidimensional framework. See Zhou et al, page 257.
Due to its unique evolutionary relevance, it is understood that pain automatically attracts attention. This study investigated attentional shifts by assessing eye movements into the direction of painful stimulation. Healthy participants were presented either a blank screen or a picture showing a natural scene while painful electrical stimuli were applied to the left or right hand. In general, painful stimulation reduced exploratory behavior as reflected by less and slower saccades as well as fewer and longer fixations. These findings are in line with previous observations of attentional biases towards pain-related information and highlight eyetracking as a valuable tool to assess involuntary attentional consequences of pain. See Schmidt et al, page 135.
The rubber hand illusion (RHI) has been shown to alter the experience of pain, although studies have yielded inconsistent results. The authors tested the influence of RHI on the intensity of pain caused by electric stimuli. The results show that noxious stimuli were experienced as more painful on the hand under the illusion. These data suggest that the link between bodily illusions and pain could be modulated by uncertainty about location of pain and affected body part. See Siedlecka et al, page 35.
Weight loss improves pain localized to weight bearing joints, but it is unknown how weight loss affects the spatial distribution of pain and associated somatic symptoms like fatigue. This research sought to determine if weight loss improves pain, affect, and somatic symptoms commonly associated with chronic pain conditions. Pain, symptom severity, depression and fibromyalgia scores improved following weight loss; men showed greater improvement than women on somatic symptoms and fibromyalgia scores. Weight loss may improve diffuse pain and comorbid symptoms commonly seen in chronic pain participants. See Schrepf et al, Page 1542.
The aim of this case-control study was to examine differences in neural correlates of pain facilitatory and inhibitory mechanisms between acute low back pain patients and healthy individuals. Pressure pain tolerance, electrical pain detection thresholds, pain ratings to repetitive suprathreshold electrical stimulation and conditioned pain modulation were assessed in 18 patients with acute low back pain and 18 healthy controls. This article presents evidence that acute low back pain patients show enhanced pain facilitation and unaltered pain inhibition compared to pain-free volunteers. This information provides new insight into the central mechanisms underlying acute low back pain. See Vuilleumier et al, Page 1313.
Tissue and nerve injury leads to the development of facilitated pain states in which the afferent traffic generated by otherwise innocuous or mildly aversive thermal and mechanical stimuli evokes a behavioral response consistent with a more intense stimulus. A variety of convergent preclinical studies have emphasized the importance of the role played by the spinal NMDA/glutamate-gated channel in the development of this facilitated state. This study examined the analgesic and behavioral profile of systemically delivered prodrug L-4- chlorokynurenine (4-Cl-KYN) and two standard compounds used in the field (MK-801 and gabapentin). Compared to other drugs tested, 4-Cl-KYN has robust anti-nociceptive effects with a better side effect profile, highlighting its potential for treating hyperpathic pain states. See Yaksh et al, page 1184.
The dorsolateral prefrontal cortex (DLPFC) is a functionally and structurally heterogeneous region and a key node of several brain networks, implicated in cognitive, affective, and sensory processing. The DLPFC is commonly activated in experimental pain studies, and shows abnormally increased function in chronic pain populations. Several studies have shown that some chronic pains are associated with decreased left DLPFC gray matter and that successful interventions can reverse this structural abnormality. Upon successful resolution of pain, these abnormalities are reversed. Understanding the underlying mechanisms and the role of this region can lead to the development of an effective therapeutic target for some chronic pain conditions. See Seminowicz and Moayedi, page 1027.
More than one-third of patients with metastatic bone disease experience moderate to severe pain, which debilitates their quality of life. Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients, due to lack of understanding of its mechanisms. In this study, the authors investigated the specific cellular mechanisms of GABA receptors (GABABRs) in the development and maintenance of CIBP in rats. See Zhou et al, page 933.
Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread pain, hyperalgesia, and other disabling symptoms. While the brain response to experimental pain in FM patients has been the object of intense investigation, the biological underpinnings of painful after-sensations (PAS) and their relation to negative affect have received little attention. In this cross-sectional cohort study, subjects with FM and healthy controls were assessed for PAS. Results show that PAS are more common and severe in FM, and are associated with clinical pain and catastrophizing. See Schreiber et al, page 855.
To determine if modest amounts of voluntary exercise improves injury-induced persistent pain and stress, this work studied how 2-hour daily access to running wheels (4 days/week for 3 weeks) altered multiple measures of pain and stress in a rat model of persistent inflammatory pain. The results show that that regular voluntary exercise effectively reduced both pain and stress. Moreover, the level of running was unrelated to the analgesic and stress reducing effects, indicating that consistent, self-regulated exercise may be more relevant than standardized activity goals. See Pitcher et al, page 687.
There are inadequate age specific data to support the use of current self-report pain scales in 3- and 4-year-old children. The authors sought to evaluate the validity and feasibility of two novel simplified scales among children undergoing venipuncture. The child is first asked whether there is pain. If yes, these faces or blocks are shown to obtain a mild, moderate, or severe rating. This method is not yet established for clinical use. The portion of this image showing the Simplified Faces Pain Scale is reprinted with permission: © 2014, CL von Baeyer. See Emmott et al, page 564.
Damage to the spinal cord or peripheral nerves can lead to the development of neuropathic pain, which causes considerable suffering and distress. This research demonstrates that reducing D-serine suppresses central sensitization and significantly alleviates peripheral nerve injury-induced chronic neuropathic pain in mice, and suggests this process is modulated by spinal sigma-1 receptors. This preclinical evidence provides a strong rationale for using D-serine antagonists to treat peripheral nerve injury-induced neuropathy. See Choi et al, page 415.
This image portrays abnormal brain responses of patients with complex regional pain syndrome (CRPS). Through an analysis of functional magnetic resonance images, this research shows that in those with CRPS, observing others’ motor actions induces abnormal neural activity in brain areas essential for sensorimotor functions and pain. These results build the cerebral basis for action-observation impairments in CRPS. See Hotta et al, page 255.
It is not uncommon for patients chronically treated with opioids to exhibit opioid induced hyperalgesia (OIH). This has been widely reported both clinically and experimentally. This work shows that in mice and rats, sustained morphine administration induces cold hyperalgesia and an up-regulation of TRPM8. The results indicate that chronic morphine upregulates TRPM8 channels, which contrasts with previous findings that acute morphine triggers TRPM8 internalization. See Gong and Jasmin, page 212.
This cover image is provided courtesy of Kathleen Sluka, Journal of Pain Editorial Board member. The image, ‘‘Color of Pain,’’ represents pain transmitting neurons that depict the color pain assessment tool. Sluka is a Journal of Pain Editorial Board member and professor of physical therapy and rehabilitation science at the University of Iowa, where she studies peripheral and central mechanisms of chronic musculoskeletal pain as well as non-pharmacological treatment for chronic pain. Additional artwork can be viewed at slukaart.wordpress.com.
Chronic pain is a major cause of suffering, disability, lost work, and health care expenses. A rat model of ganglionic field stimulation was developed to test analgesic effects in the context of neuropathic pain. This work demonstrates that electrical stimulation of the dorsal root ganglion in rats reverses neuropathic pain behavior and provides a rewarding effect to animals with spontaneous neuropathic pain. This image shows histology findings in animals with GFS electrode placement. See Pan et al, page 1349.
Stimulation-evoked antinociception from the anterior pretectal nucleus (APtN) activates two descending inhibitory pathways, one relaying in the ipsilateral lateral paragigantocellular nucleus (LPGi) and another relaying sequentially in the contralateral deep mesencephalic (DpMe) and pedunculopontine tegmental (PPTg) nuclei. The images show the locations of an electrode track in the APtN and injection site into the DpMe, PPTg and LPGi. See Genaro and Prado, page 1156.
Migraine is prevalent and disabling yet is poorly understood. One way to better understand migraine is to examine clinical characteristics and potential biomarkers such as gamma-aminobutyric acid (GABA). This work explored whether relevant disease characteristics of migraine are associated with brain GABA levels. This illustration, provided by the authors, was stylized from an output of the editing process of GABA, particularly of the creatine signal after frequency correction. See Aguila et al, page 1058.
This cover image is provided courtesy of Kathleen Sluka, Journal of Pain Editorial Board member. Sluka, a professor of physical therapy and rehabilitation science at the University of Iowa, studies peripheral and central mechanisms of chronic musculoskeletal pain as well as non-pharmacological treatment for chronic pain. Outside of her laboratory work in the Carver College of Medicine, she combines her interests in art and biology to paint science-related images. This painting is titled "Metallic Neurons."
Drugs interacting with TRP channels are of great therapeutic potential. In this study, the authors established cutaneous pain and hyperalgesia using the TRPA1 agonist trans-cinnamaldehyde. This work showed that the frequently used topical counterirritant and TRPM8 agonist L-menthol decreased evoked pain, hyperalgesia, and inflammation, indicating both direct and indirect antinociceptive mechanisms. See Andersen et al, page 919.
Chemotherapy-induced peripheral neuropathy is a disruptive and persistent side-effect of cancer treatment with paclitaxel. This clinical problem is steadily on the rise as the number of long-term cancer survivors increases. This paper shows that activation of innate immunity by paclitaxel results in a sequence of signaling events that results in the infiltration of the dorsal root ganglia by activated macrophages. See Zhang et al, page 775.
It is recognized that the clinical manifestation of migraines is heterogeneous, but the neurophysiological mechanisms underlying clinical manifestation remain largely unknown. Magnetoencephalography, a relatively new modality for noninvasive assessment of functional brain activation, has been used to find that there are significant neuromagnetic abnormalities in the motor cortex of childhood migraine sufferers. In this study, the authors document that neuromagnetic signals are localized to the middle occipital and ipsilateral sensorimotor cortices in migraine subjects, but not in healthy controls. See Xiang et al, page 694.
Physical exercise can attenuate neuropathic pain, but the exact mechanism underlying exercise-induced hypoalgesia remains unclear. This research considered the role of epigenetics, processes that lead to stable and/or heritable changes in gene function without any concomitant DNA sequence changes. This image shows changes of microglia in mice following treadmill running. The authors conclude that epigenetic modification causing hyperacetylation of H3K9 in activated microglia is important in producing exercise-induced hypoalgesia. See Kami et al, page 588.
Epidemiological studies and meta-analyses report a strong relationship between chronic pain and abnormalities in glucose metabolism, but the exact relationship between chronic pain and insulin resistance in type-2-diabetes (T2D) remains unknown. Using a model of neuropathic thermal and tactile hypersensitivity induced by chronic constriction sciatic nerve injury in rats, the authors’ research concluded that nerve injuries in genetically susceptible individuals may accelerate the development of insulin resistance as in T2D. See Zhai et al, page 404.
These images show the involvement of alpha-2 adrenoceptors in the restorative effect of repetitive diluted bee venom (DBV) treatment on the oxaliplatin-induced reduction in both the numbers and density of intraepidermal nerve fibers. In this study, the authors report that repetitive acupoint treatment with DBV can be a potential strategy for the management of chemotherapy-induced neuropathy. See Yeo et al, page 298.
The majority of patients who undergo surgery experience acute pain that resolves as the wound heals. However, 5-15% of patients following common surgeries exhibit very slow recovery and experience persistent pain. The mechanisms responsible for recovery are not clear. In this animal study, the authors measure the impact of blocking or disrupting descending noradrenergic input on resolution of evoked and spontaneous pain-related behaviors and spinal glial activation in a plantar incision model that lacks injury to major peripheral nerves and typically resolves within days. This image depicts microglial (blue) and astrocyte (green) activation in the ipsilateral dorsal medial spinal cord of rats 21 days following plantar incision with (lower panels) or without (middle panels) chronic spinal blockade of alpha 2 adrenergic receptor signaling. Top panels depict images from rats without surgery. See Arora et al, page 190.
Chronic back pain (CBP) is associated with circumscribed atrophy in gray matter (GM) predominantly localized in areas of the socalled ‘‘pain matrix’’ and the prefrontal cortex. Previous studies reported inconsistent results on the alteration of brain areas in chronic pain conditions. This study used voxel-based morphometry for high resolution magnetic resonance images to investigate the association of CBP and regional GM volume in 111 individuals with CBP and 432 pain free controls. The results may contribute to our understanding of the transition from acute to chronic pain in some areas of the brain. See Fritz et al, page 111.
Although preclinical and clinical data strongly support an association between the amygdala and chronic pain by the presence of mood and cognitive disturbances in affected individuals, little attention has been paid to morphometric measurement of the structure in patients with chronic low back pain (CLBP). The study by Mao and Yang found that patients with CLBP had statistically significantly smaller normalized volumes of the bilateral amygdala, as compared with healthy controls, with a greater involvement of the left side. This image portrays vector graphs of the amygdala according to surface measures in traditional vertex analysis. See Mao and Yang, page 1366.
Acceptance and Commitment Therapy (ACT) aims to increase the behavioral flexibility of individuals facing painful situations. Pain acceptance is the willingness to experience pain while engaging in valued activities. It is often measured using the Chronic Pain Acceptance Questionnaire. Previous analyses identified three patient clusters which differed across measures of patient functioning in meaningful ways. In this issue, Rovner et al present clustering using Latent Class Analysis. This cover image, a collaborative piece between ACT psychologist and artist Rikke Kjelgaard and author Graciela Rovner, is metaphorically related to ACT. See Rovner et al, page 1095.
Although ketamine is beneficial in treating complex regional pain syndrome (CRPS), a subset of patients respond poorly to therapy. This work investigated treatment-induced microRNA (miRNA) changes and their predictive validity in determining treatment outcome by assessing miRNA changes in whole blood from CRPS patients. This figure represents posttreatment samples, demonstrating that 43 miRNAs differed between responders and poor responders. See Douglas et al, page 814.
The use of placebo to reduce pain is well documented; however, knowledge of the neural mechanisms underlying placebo analgesia (PA) remains incomplete. This study used fMRI data from 30 healthy subjects and dynamic causal modeling to investigate changes in effective connectivity associated with the placebo analgesic response. Knowledge of these mechanisms highlights the importance of integrated neural networks in the understanding of pain modulation. See Sevel et al, page 760.
Acute pain following inguinal hernia repair can be difficult to treat. There is a need for improved understanding of the mechanisms mediating acute postoperative pain and for development of more effective pain management protocols. The authors report, for the first time, the development of a novel, anatomically relevant rat model to facilitate improved understanding and treatment of acute postoperative pain following inguinal hernia repair. See Bree et al, page 421.
Pruritus is a primary complaint associated with dry skin and other dermatoses that compromise skin barrier integrity, such as atopic dermatitis and psoriasis. The mechanisms by which dry skin generates itch are unclear. This study examines the underlying neurobiological mechanisms. See Valtcheva et al, page 346.
These images demonstrate sectioned spinal cords in transected mice. To determine whether an injury-specific promoter can enhance antinociception and drive expression of mu-opioid receptor in specific populations of afferent neurons, as opposed to constitutive expression with a nonspecific promoter, the authors compared animals infected with a galanin promoter virus to those infected with a cytomegalovirus promoter virus. This article presents evidence that promoter selection is an important component in successful gene expression in an injury- and population-specific manner. See Smith et al, page 283.
Motivational accounts of pain behavior and disability suggest that attempts to avoid or control pain may paradoxically result in heightened attention to pain-related information. This study investigated the impact of attempts to control pain on somatosensory processing at the pain location. The results provide further insight into the motivational mechanisms of pain-related attention and point to the negative consequences of trying to control uncontrollable pain. See Durnez and Van Damme, page 135.
These immunohistochemistry images were part of a study published in The Journal of Pain that elucidated the analgesic effect of acupuncture in a mouse pain model. The image is provided courtesy of Y Li et al (Li Y, Zhang Haijun, Zhang Hongmei, Kosturakis AK, Jawad AB, Dougherty, PM. Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy. J Pain 15:712-725, 2014.). See Y Li et al, page 712.
Disorders of pain neural systems are frequently chronic and, when recalcitrant to treatment, can severely degrade the quality of life. The pain pathway begins with sensory neurons in dorsal root or trigeminal ganglia, and the neuronal subpopulations that express the TRPV1 ion channel transduce sensations of painful heat and inflammation. These play a fundamental role in clinical pain. See Goswami et al, page 1338.
Emerging evidence shows that chronic musculoskeletal pain is associated with anatomic and functional abnormalities in gray matter. However, little research has investigated the relationship between chronic musculoskeletal pain and white matter. In this study, the authors used whole- brain tract-based spatial statistics and region-of-interest analyses of diffusion tensor imaging data to demonstrate that patients with chronic musculoskeletal pain exhibit several abnormal metrics of white matter integrity, compared with healthy controls. See Lieberman et al, page 1110.
Although functional magnetic resonance imaging (fMRI) has been proposed as a method to elucidate pain-related biomarkers, little information exists related to psychometric properties of fMRI findings. The purpose of this study was to assess the test-retest reliability of pain-related brain activity and how it compares to the reliability of self-report. Findings suggest that fMRI is a valuable tool for measuring pain mechanisms but did not show an adequate level of test-retest reliability to potentially act as a surrogate for individuals’self-report of pain. See Letzen et al, page 1008.
Whiplash accounts for approximately 80% of the soft tissue injuries incurred in motor vehicle accidents. About 15 to 25%of individuals who sustain whiplash injuries remain permanently disabled. Some studies have reported that more severe pain following injury is associated with more severe disability. In this study, the authors examined whether measures of movement-evoked pain might account for unique variance in measures of disability beyond the variance accounted for by measures of spontaneous pain. See Mankovsky-Arnold et al, page 967. Cervical column cover image is courtesy of Andrew J. Holman.
Using a matched pain intensity paradigm, where pain intensity was kept constant across participants but pain unpleasantness was left free to vary among participants, this report studied the relationship between pain unpleasantness and pain-evoked brain activity in healthy men and women separately. This article presents neuroimaging findings demonstrating that subjective unpleasantness ratings are associated with different pain-evoked brain responses between the sexes, which have potentially important implications regarding sex differences in the risk of developing chronic pain. See Girard-Tremblay et al, page 867.
Paclitaxel is the front-line chemotherapeutic agent used to treat many tumors, including those of the breast, ovary, and lung. Peripheral neuropathy is the major dose-limiting side effect of paclitaxel and can force dose reduction or even discontinuation of therapy, thus impacting survival in cancer patients. This research tests the contribution of the toll-like receptors, TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. See Li et al, page 712.
Central neuropathic pain (CNP) is believed to be accompanied by increased activation of the sensorimotor cortex. This study compares the electroencephalography (EEG) activity of spinal cord–injured patients with CNP to that of spinal cord–injured patients with no pain and also to that of able-bodied people. The study shows that the presence of CNP itself leads to frequency-specific EEG signatures that could be used to monitor CNP and inform neuromodulatory treatments of this type of pain. See Vuckovic et al, page 645.
Despite accumulating evidence of the clinical effectiveness of acupuncture, its mechanism remains largely unclear. It is assumed that molecular signaling around the acupuncture needled area is essential for initiating the effect of acupuncture. Results from this study show that extracellular signal–regulated kinase phosphorylation following acupuncture needling is a biochemical hallmark initiating the effect of acupuncture including analgesia. See Park et al, page 535.
In this research, patients with irritable bowel syndrome rated pain and underwent functional magnetic resonance imaging brain scanning during experimentally induced rectal distension. The results show that expectations for pain can be verbally manipulated to produce placebo analgesia. See Craggs et al, page 435.
This study examined the role of the glial–neuronal G protein–coupled receptor kinase 2 (GRK2) pathway in the development of trigeminal neuropathic pain. See Won et al, page 250.
The aim of this study was to determine whether α1-adrenoceptor expression was upregulated on surviving peptidergic, nonpeptidergic, and myelinated nerve fiber populations in the skin after chronic constriction injury of the sciatic nerve in rats. These findings indicate that peripheral nerve injury provokes upregulation of α1-adrenoceptors on surviving nociceptive afferents and epidermal cells in the skin. See Drummond et al, page 188.
Chronic pain is influenced by biological, psychological, social, and cultural factors. This work investigated potential roles for combinations of genetic and psychological factors as predictors of different exercise-induced shoulder pain phenotypes. See George et al, page 68..
This image represents the use of magnetoencephalography signals to focus on the spectral and spatial signatures of cortical dysfunction in adolescents with migraine. The spread of abnormal ictal brain activation in both low- and high-frequency ranges triggered by movements may play a key role in the cascade of migraine attacks. See Xiang, et al, page 1553.
Immunofluorescence imaging was used in this study, which demonstrates the detailed distribution of calcitonin gene-related peptide (CGRP) and its receptor in the dura mater. Results suggest that CGRP is expressed in C-fibers and may act on A-fibers, rodent mast cells, and vascular smooth muscle cells that express the CGRP receptor. See Eftekhari, et al, page 1289.
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe side effect accompanying paclitaxel chemotherapy, and effective treatment is lacking. This research suggests that blocking chemokine monocyte chemoattractant protein-1 and its cognate receptor CCR2 could be a new therapeutic strategy to prevent or reverse paclitaxel CIPN. See Zhang, et al, page 1031.
Pain is a cardinal symptom of inflammation. In the early stages, neutrophils and monocytes/macrophages are recruited as part of the innate immune response. Because pain and leukocyte recruitment commonly occur simultaneously, all leukocytes are presumed to contribute to the generation of pain. To study the molecular links between the recruitment of leukocyte subpopulations and inflammatory hyperalgesia, the authors used local injection of specific chemokines as a tool for more selective leukocyte recruitment. See Pflücke, et al, page 897.
In the central nervous system, the rostroventromedial medulla (RVM) is an important component of the endogenous descending pain regulating system. Neurons in the RVM send axonal projections to the superficial laminae of the spinal dorsal horn, which is known to be critical for nociceptive processing. This study enhances the understanding of the modulation of nociceptive information in the descending pain regulating system. See Chen, et al, page 778.
Intravenous injection of STZ in Wistar rats led to selective degeneration of insulin-roducing pancreatic ß-cells, elevated blood glucose, and mechanical hyperalgesia. See Shaqura, et al, page 720.
This image demonstrates heat map illustration of gene expression profiles in mice. The nociceptive and antinociceptive properties of CXBH recombinant inbred mice and gene expression differences that may underlie nociceptive tolerance were examined. See Kasai and Ikeda, page 648.
Resting state functional magnetic resonance imaging was used to study alterations in the default mode network of failed back surgery syndrome (FBSS) patients as compared to healthy subjects. The authors report alterations in the default mode network of chronic low back pain patients with FBSS, as compared to healthy participants. See Kornelsen, et al, page 483.
A novel, high-definition, transcranial direct current stimulation technique that is capable of a focal and targeted stimulation has been shown to provide a reduction in overall perceived pain in fibromyalgia patients. This image demonstrates placement of electrodes and electric field distribution. See Villamar, et al, page 371.
A total of 28 fMRI studies, which consisted of 51 acupuncture and 10 tactile stimulation experiments, were selected for meta-analysis as part of a review to better understand acupuncture needle stimulation and its effects on specific activity changes in different brain regions. Shown are brain areas associated with acupuncture stimulation that exhibited increased (red) and decreased (blue) activity. See Chae, et al, page 215.
The contribution of spinal astrocytes and astrocyte gap junctions to oxaliplatin-induced mechanical hypersensitivity was explored. Results show that spinal astrocyte gap junctions play an important role in the induction of oxaliplatin neuropathy. See Yoon, et al, page 205.
Nerve injury results in the activation and recruitment of inflammatory cells leading to changes in the microenvironment that are associated with the development of neuropathic pain. In this image, cell staining and flow cytometry analysis for several inflammatory cell types is shown. See Liou, et al, page 24.
The nonselective sodium channel blocker lidocaine is widely used as a local anesthetic but also systemically for treatment of postoperative and neuropathic pain. In this study, injections of lidocaine .1% or saline .9% were performed intradermally directly under the stimulation needles at the foot. Results suggest that microneurography can be used to assess pharmacological effects on single C-fibers directly in humans. See Kankel, et al, page 1232.
The role of traditional Chinese medicine—acupuncture and herbs—in conjunction with a validated psychosocial self-care intervention for treating chronic temporomandibular disorder-associated pain was examined. Findings suggest this approach is safe and effective alone or subsequent to standard psychosocial interventions. See Ritenbaugh, et al, page 1075.
Variation among counties in estimated mean milligrams of opioids dispensed, per county resident, by retail pharmacies in the United States during 2008. County populations are tandardized by age and gender; opioids include the eight most commonly prescribed and amounts dispensed are expressed in morphine equivalent units. See MacDonald, et al, page 988.
A better understanding of the mechanisms that drive chronic pain is necessary to develop new treatment options and to discover strategies for treating or preventing chronic pain. Mitogen-activated protein kinases (MAPKs) are pivotal in the development of chronic allodynia in rodent models of neuropathic pain. In this issue, Landry et al show that the major phosphatases (MKPs) that limit the activation of MAPKs are also involved in the mechanism underlying the development of chronic pain. This confocal microscopy image shows MKP-1 expression in spinal cord neurons. See Landry, et al, page 836.
Substance P (red) and IB4 (1) (green) central terminals are spatially segregated in the dorsal horn of a mouse spinal cord. Substance P terminals are located in the superficial dorsal horn (I-IIo: laminae I and outer II) while IB4 (1) terminals are concentrated in the inner part of lamina II (IIi). See Ye, et al, page 524.
Models of effective connectivity involving pain-related processes were estimated with functional magnetic resonance imaging data from chronic pain and healthy populations. Models were estimated in both hemispheres, and although similar, fibromyalgia was associated with unique models of pain-related processes, providing evidence for overlap of brain mechanisms that process information related to pain in subjects with and without fibromyalgia. See Craggs, et al, page 390.
Paclitaxel often induces persistent painful neuropathy as its most common treatment limiting side effect. Little is known concerning the underlying mechanisms. Given the prominent role of glial cells in many types of neuropathic pain, this work investigated the morphological and functional changes of spinal astrocytes and microglia in a rat model of paclitaxel-induced neuropathy. This image portrays immunohistochemical stainings. See Zhang, et al, page 293.
Electrotherapy techniques allow for the instant electricity to targeted brain regions with minimally invasive methods that are effective in managing some forms of chronic pain, by inducing changes in cortical excitability that may be related to changes in concentrations of glutamate and gamma-aminobutyric acid. Research shows that high definition transcranial direct current stimulation allows for focal delivery to discrete regions of the cortex. See Borckardt, et al, page 112.
The role of endogenousnoradrenaline on glial and neuronal plasticity in the spinal cord in rats after peripheral nerve injury was studied. Depletion of noradrenaline led to exagerrated responses of microglia and astrocytes in the spinal cord. Images were pseudocolored to distinguish labeling of proteins. See Hayashida, et al, page 49.
The primary symptom of fibromyalgia is chronic, widespread pain, but patients also report decreased concentration and memory. The hypothesis that response-inhibition and pain perception may rely on partially overlapping networks, and that resources taken up by pain processing in chronic pain patients may not be available for executive functioning tasks, was examined using functional magnetic resonance imaging. See Glass, et al, page 1219.
Glial cell line-derived neurotrophic factor (GDNF), a survival promoting factor for subset of nociceptive small-diameter neurons, has been shown to exert analgesic effects on neuropathic pain. This study investigated the site-specific analgesic effects of GDNF in the neuropathic pain state, using lentiviral vector-mediated GDNF overexpression in mice with left fifth lumbar spinal nerve ligation as a neuropathic pain model. See Takasu, et al, page 1130.
Epidermal nerve fibers in a patient with chronic bortezomib-related neuropathy are portrayed. Patients who had previously been treated with bortezomib and who were experiencing ongoing pain consented to recurring quantitative sensory testing. The results demonstrate a persistent, painful peripheral neuropathy in patients treated with bortezomib. See Boyette-Davis, et al, page 1017.
In the article "Factors Affecting Placebo Acceptability: Deception, Outcome, And Disease Severity," Kisaalita et al asked participants to characterize acceptability of a placebo analgesic intervention using three descriptors: entirely acceptable, marginally acceptable, and entirely unacceptable placebo. Results suggest that deceptive placebos may be acceptable dependent on the level of treatment effectiveness and severity/negative consequences.
To provide better postoperative pain control, there is a need to understand the factors that contribute to the development of pain after surgery. Leukemia inhibitory factor (LIF) is a pleiotropic cytokine released from tissues after injury. This image demonstrates activation of STAT3 in L4-L5 dorsal root ganglion (DRG) primary cultures by LIF. The study hypothesized that LIF expression in skin, muscle, and DRG would increase after plantar incision. See Spofford et al.
High resolution finite element model of brain activation during transcranial direct current stimulation (tDCS) in fibromyalgia. In this study, clinical effects were correlated with predictions of induced cortical currents. The results demonstrate the utility of computer modeling in the rational interpretation and design of therapies with tDCS. Brain modulation is shown in false color. See Mendonca, et al, page 610.
Many oncology outpatients with bone metastasis report unrelieved pain that interferes with daily functioning and quality of life. This figure shows a random selection of individual trajectories of average pain (left panel) and worst pain (right panel) across the 6 week study period. See "Trajectories Of Pain And Analgesics In Oncology Outpatients With Metastatic Bone Pain," by Langford, et al.
The relationships between substance use disorder (SUD) history and 12-month outcomes among primary care patients with chronic noncancer pain (CNCP) were explored. Patients were enrolled in a randomized trial of collaborative care intervention versus treatment-as-usual to improve physical and emotional function. Findings show that CNCP patients with a SUD history report poorer pain-related functioning and are less likely to experience significant improvements. Providers should assess for SUD status and provide more intensive interventions for these patients.
Temperature data are demonstrated in a study of the anesthetic ropivacaine, which may promote recovery after surgery. Relief of acute and long-term postoperative pain is essential to patients undergoing surgery. Recovery may be enhanced by using perioperative ropivacaine, since it may limit the risk of chronic pain and postoperative complications.
The expression of NF-κB in the spinal cord is associated with neuropathic pain, but little is known about its expression beyond the spinal cord. This research examined a spatial and temporal pattern of the NF-κB expression in both spinal and supraspinal regions, and presents a spatiotemporal mapping of these areas following peripheral injury.