Advertisement

From Peripheral to Central: The Role of ERK Signaling Pathway in Acupuncture Analgesia

  • Ji-Yeun Park
    Affiliations
    Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea

    Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
    Search for articles by this author
  • Jongbae J. Park
    Affiliations
    Asian Medicine and Acupuncture Research, Department of Physical Medicine and Rehabilitation, Chapel Hill, North Carolina

    Center for Pain Research and Innovation, UNC School of Dentistry, Chapel Hill, North Carolina
    Search for articles by this author
  • Songhee Jeon
    Affiliations
    Dongguk University Research Institute of Biotechnology, Seoul, Republic of Korea
    Search for articles by this author
  • Ah-Reum Doo
    Affiliations
    Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea
    Search for articles by this author
  • Seung-Nam Kim
    Affiliations
    Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea

    Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
    Search for articles by this author
  • Hyangsook Lee
    Affiliations
    Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea
    Search for articles by this author
  • Younbyoung Chae
    Affiliations
    Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea

    Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
    Search for articles by this author
  • William Maixner
    Affiliations
    Center for Pain Research and Innovation, UNC School of Dentistry, Chapel Hill, North Carolina
    Search for articles by this author
  • Hyejung Lee
    Affiliations
    Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea

    Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
    Search for articles by this author
  • Hi-Joon Park
    Correspondence
    Address reprint requests to Hi-Joon Park, KMD, PhD, Kyung Hee University, Acupuncture and Meridian Science Research Center, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
    Affiliations
    Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea

    Carolina Asia Center, UNC-Chapel Hill, Chapel Hill, North Carolina
    Search for articles by this author
Published:February 12, 2014DOI:https://doi.org/10.1016/j.jpain.2014.01.498

      Abstract

      Despite accumulating evidence of the clinical effectiveness of acupuncture, its mechanism remains largely unclear. We assume that molecular signaling around the acupuncture needled area is essential for initiating the effect of acupuncture. To determine possible bio-candidates involved in the mechanisms of acupuncture and investigate the role of such bio-candidates in the analgesic effects of acupuncture, we conducted 2 stepwise experiments. First, a genome-wide microarray of the isolated skin layer at the GB34-equivalent acupoint of C57BL/6 mice 1 hour after acupuncture found that a total of 236 genes had changed and that extracellular signal–regulated kinase (ERK) activation was the most prominent bio-candidate. Second, in mouse pain models using formalin and complete Freund adjuvant, we found that acupuncture attenuated the nociceptive behavior and the mechanical allodynia; these effects were blocked when ERK cascade was interrupted by the mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) inhibitor U0126 (.8 μg/μL). Based on these results, we suggest that ERK phosphorylation following acupuncture needling is a biochemical hallmark initiating the effect of acupuncture including analgesia.

      Perspective

      This article presents the novel evidence of the local molecular signaling in acupuncture analgesia by demonstrating that ERK activation in the skin layer contributes to the analgesic effect of acupuncture in a mouse pain model. This work improves our understanding of the scientific basis underlying acupuncture analgesia.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Abraham T.S.
        • Chen M.L.
        • Ma S.X.
        TRPV1 expression in acupuncture points: Response to electroacupuncture stimulation.
        J Chem Neuroanat. 2011; 41: 129-136
        • Ahmad S.
        • Ahmad A.
        • McConville G.
        • Schneider B.K.
        • Allen C.B.
        • Manzer R.
        • Mason R.J.
        • White C.W.
        Lung epithelial cells release ATP during ozone exposure: Signaling for cell survival.
        Free Radic Biol Med. 2005; 39: 213-226
        • Angst M.S.
        • Phillips N.G.
        • Drover D.R.
        • Tingle M.
        • Ray A.
        • Swan G.E.
        • Lazzeroni L.C.
        • Clark J.D.
        Pain sensitivity and opioid analgesia: A pharmacogenomic twin study.
        Pain. 2012; 153: 1397-1409
        • Berman B.M.
        • Langevin H.M.
        • Witt C.M.
        • Dubner R.
        Acupuncture for chronic low back pain.
        N Engl J Med. 2010; 363: 454-461
        • Boureux A.
        • Vignal E.
        • Faure S.
        • Fort P.
        Evolution of the Rho family of ras-like GTPases in eukaryotes.
        Mol Biol Evol. 2007; 24: 203-216
        • Burgess S.T.
        • McNeilly T.N.
        • Watkins C.A.
        • Nisbet A.J.
        • Huntley J.F.
        Host transcription factors in the immediate pro-inflammatory response to the parasitic mite Psoroptes ovis.
        PLoS One. 2011; 6: e24402
        • Bustelo X.R.
        • Sauzeau V.
        • Berenjeno I.M.
        GTP-binding proteins of the Rho/Rac family: Regulation, effectors and functions in vivo.
        Bioessays. 2007; 29: 356-370
        • Cabioglu M.T.
        • Cetin B.E.
        Acupuncture and immunomodulation.
        Am J Chin Med. 2008; 36: 25-36
        • Chen C.Y.
        • Chern R.S.
        • Liao M.H.
        • Chang Y.H.
        • Hsu J.Y.
        • Chien C.H.
        The possible neuronal mechanism of acupuncture: Morphologicalevidence of the neuronal connection between groin A-Shi point and uterus.
        Evid Based Complement Alternat Med. 2013; 2013: 429186
        • Chiquet M.
        • Renedo A.S.
        • Huber F.
        • Fluck M.
        How do fibroblasts translate mechanical signals into changes in extracellular matrix production?.
        Matrix Biol. 2003; 22: 73-80
        • Meridians & Acupoints Compilation Committee of Korean Oriental Medical Colleges
        Principles of Meridians & Acupoints: A Guidebook for College Students.
        Eui Bang Publishing Co, Wonju, Republic of Korea2009
        • Dai Y.
        • Iwata K.
        • Fukuoka T.
        • Kondo E.
        • Tokunaga A.
        • Yamanaka H.
        • Tachibana T.
        • Liu Y.
        • Noguchi K.
        Phosphorylation of extracellular signal-regulated kinase in primary afferent neurons by noxious stimuli and its involvement in peripheral sensitization.
        J Neurosci. 2002; 22: 7737-7745
        • Davies S.P.
        • Reddy H.
        • Caivano M.
        • Cohen P.
        Specificity and mechanism of action of some commonly used protein kinase inhibitors.
        Biochem J. 2000; 351: 95-105
        • Davis R.T.
        • Churchill D.L.
        • Badger G.J.
        • Dunn J.
        • Langevin H.M.
        A new method for quantifying the needling component of acupuncture treatments.
        Acupunct Med. 2012; 30: 113-119
        • Favata M.F.
        • Horiuchi K.Y.
        • Manos E.J.
        • Daulerio A.J.
        • Stradley D.A.
        • Feeser W.S.
        • Van Dyk D.E.
        • Pitts W.J.
        • Earl R.A.
        • Hobbs F.
        • Copeland R.A.
        • Magolda R.L.
        • Scherle P.A.
        • Trzaskos J.M.
        Identification of a novel inhibitor of mitogen-activated protein kinase kinase.
        J Biol Chem. 1998; 273: 18623-18632
        • Ferenz K.B.
        • Gast R.E.
        • Rose K.
        • Finger I.E.
        • Hasche A.
        • Krieglstein J.
        Nerve growth factor and brain-derived neurotrophic factor but not granulocyte colony-stimulating factor, nimodipine and dizocilpine, require ATP for neuroprotective activity after oxygen-glucose deprivation of primary neurons.
        Brain Res. 2012; 1448: 20-26
        • Garrington T.P.
        • Johnson G.L.
        Organization and regulation of mitogen-activated protein kinase signaling pathways.
        Curr Opin Cell Biol. 1999; 11: 211-218
        • Gim G.T.
        • Lee J.H.
        • Park E.
        • Sung Y.H.
        • Kim C.J.
        • Hwang W.W.
        • Chu J.P.
        • Min B.I.
        Electroacupuncture attenuates mechanical and warm allodynia through suppression of spinal glial activation in a rat model of neuropathic pain.
        Brain Res Bull. 2011; 86: 403-411
        • Goldman N.
        • Chen M.
        • Fujita T.
        • Xu Q.
        • Peng W.
        • Liu W.
        • Jensen T.K.
        • Pei Y.
        • Wang F.
        • Han X.
        • Chen J.F.
        • Schnermann J.
        • Takano T.
        • Bekar L.
        • Tieu K.
        • Nedergaard M.
        Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture.
        Nat Neurosci. 2010; 13: 883-888
        • Guo Z.L.
        • Longhurst J.C.
        Activation of reciprocal pathways between arcuate nucleus and ventrolateral periaqueductal gray during electroacupuncture: involvement of VGLUT3.
        Brain Res. 2010; 1360: 77-88
        • Hahm E.T.
        • Lee J.J.
        • Lee W.K.
        • Bae H.S.
        • Min B.I.
        • Cho Y.W.
        Electroacupuncture enhancement of natural killer cell activity suppressed by anterior hypothalamic lesions in rats.
        Neuroimmunomodulation. 2004; 11: 268-272
        • Hirano T.
        • Zeredo J.L.
        • Kimoto M.
        • Moritaka K.
        • Nasution F.H.
        • Toda K.
        Disinhibitory involvement of the anterior cingulate cortex in the descending antinociceptive effect induced by electroacupuncture stimulation in rats.
        Am J Chin Med. 2008; 36: 569-577
        • Hurt J.K.
        • Zylka M.J.
        PAPupuncture has localized and long-lasting antinociceptive effects in mouse models of acute and chronic pain.
        Mol Pain. 2012; 8: 28
        • Ilfeld B.M.
        Continuous peripheral nerve blocks: A review of the published evidence.
        Anesth Analg. 2011; 113: 904-925
        • Johnson G.L.
        • Lapadat R.
        Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases.
        Science. 2002; 298: 1911-1912
        • Jou N.T.
        • Ma S.X.
        Responses of nitric oxide-cGMP release in acupuncture point to electroacupuncture in human skin in vivo using dermal microdialysis.
        Microcirculation. 2009; 16: 434-443
        • Katz S.
        • Boland R.
        • Santillan G.
        Modulation of ERK 1/2 and p38 MAPK signaling pathways by ATP in osteoblasts: Involvement of mechanical stress-activated calcium influx, PKC and Src activation.
        Int J Biochem Cell Biol. 2006; 38: 2082-2091
        • Kim D.H.
        Huangdi's Internal Classic.
        Eui Sung Dang, Seoul2002
        • Kim H.Y.
        • Wang J.
        • Lee I.
        • Kim H.K.
        • Chung K.
        • Chung J.M.
        Electroacupuncture suppresses capsaicin-induced secondary hyperalgesia through an endogenous spinal opioid mechanism.
        Pain. 2009; 145: 332-340
        • Kim W.
        • Kim S.K.
        • Min B.I.
        Mechanisms of electroacupuncture-induced analgesia on neuropathic pain in animal model.
        Evid Based Complement Alternat Med. 2013; 2013: 436913
        • Kinjo S.
        • Lim E.
        • Sands L.P.
        • Bozic K.J.
        • Leung J.M.
        Does using a femoral nerve block for total knee replacement decrease postoperative delirium?.
        BMC Anesthesiol. 2012; 12: 4
        • Kippenberger S.
        • Bernd A.
        • Loitsch S.
        • Guschel M.
        • Muller J.
        • Bereiter-Hahn J.
        • Kaufmann R.
        Signaling of mechanical stretch in human keratinocytes via MAP kinases.
        J Invest Dermatol. 2000; 114: 408-412
        • Kong J.
        • Fufa D.T.
        • Gerber A.J.
        • Rosman I.S.
        • Vangel M.G.
        • Gracely R.H.
        • Gollub R.L.
        Psychophysical outcomes from a randomized pilot study of manual, electro, and sham acupuncture treatment on experimentally induced thermal pain.
        J Pain. 2005; 6: 55-64
        • Kook S.H.
        • Jang Y.S.
        • Lee J.C.
        Involvement of JNK-AP-1 and ERK-NF-kappaB signaling in tension-stimulated expression of type I collagen and MMP-1 in human periodontal ligament fibroblasts.
        J Appl Physiol. 2011; 111: 1575-1583
        • Laboureau J.
        • Dubertret L.
        • Lebreton-De Coster C.
        • Coulomb B.
        ERK activation by mechanical strain is regulated by the small G proteins rac-1 and rhoA.
        Exp Dermatol. 2004; 13: 70-77
        • Langevin H.M.
        • Bouffard N.A.
        • Badger G.J.
        • Churchill D.L.
        • Howe A.K.
        Subcutaneous tissue fibroblast cytoskeletal remodeling induced by acupuncture: Evidence for a mechanotransduction-based mechanism.
        J Cell Physiol. 2006; 207: 767-774
        • Langevin H.M.
        • Bouffard N.A.
        • Churchill D.L.
        • Badger G.J.
        Connective tissue fibroblast response to acupuncture: Dose-dependent effect of bidirectional needle rotation.
        J Altern Complement Med. 2007; 13: 355-360
        • Langevin H.M.
        • Bouffard N.A.
        • Fox J.R.
        • Palmer B.M.
        • Wu J.
        • Iatridis J.C.
        • Barnes W.D.
        • Badger G.J.
        • Howe A.K.
        Fibroblast cytoskeletal remodeling contributes to connective tissue tension.
        J Cell Physiol. 2010; 226: 1166-1175
        • Langevin H.M.
        • Churchill D.L.
        • Cipolla M.J.
        Mechanical signaling through connective tissue: A mechanism for the therapeutic effect of acupuncture.
        FASEB J. 2001; 15: 2275-2282
        • Langevin H.M.
        • Churchill D.L.
        • Wu J.
        • Badger G.J.
        • Yandow J.A.
        • Fox J.R.
        • Krag M.H.
        Evidence of connective tissue involvement in acupuncture.
        FASEB J. 2002; 16: 872-874
        • Lee D.J.
        • Rosenfeldt H.
        • Grinnell F.
        Activation of ERK and p38 MAP kinases in human fibroblasts during collagen matrix contraction.
        Exp Cell Res. 2000; 257: 190-197
        • Libert C.
        Inflammation: A nervous connection.
        Nature. 2003; 421: 328-329
        • Lim J.H.
        • Gibbons H.M.
        • O'Carroll S.J.
        • Narayan P.J.
        • Faull R.L.
        • Dragunow M.
        Extracellular signal-regulated kinase involvement in human astrocyte migration.
        Brain Res. 2007; 1164: 1-13
        • Lin J.G.
        • Chen W.L.
        Acupuncture analgesia: A review of its mechanisms of actions.
        Am J Chin Med. 2008; 36: 635-645
        • Marinari B.
        • Costanzo A.
        • Viola A.
        • Michel F.
        • Mangino G.
        • Acuto O.
        • Levrero M.
        • Piccolella E.
        • Tuosto L.
        Vav cooperates with CD28 to induce NF-kappaB activation via a pathway involving Rac-1 and mitogen-activated kinase 1.
        Eur J Immunol. 2002; 32: 447-456
        • Mavrommatis C.I.
        • Argyra E.
        • Vadalouka A.
        • Vasilakos D.G.
        Acupuncture as an adjunctive therapy to pharmacological treatment in patients with chronic pain due to osteoarthritis of the knee: A 3-armed, randomized, placebo-controlled trial.
        Pain. 2012; 153: 1720-1726
        • Mi W.L.
        • Mao-Ying Q.L.
        • Wang X.W.
        • Li X.
        • Yang C.J.
        • Jiang J.W.
        • Yu J.
        • Wang J.
        • Liu Q.
        • Wang Y.Q.
        • Wu G.C.
        Involvement of spinal neurotrophin-3 in electroacupuncture analgesia and inhibition of spinal glial activation in rat model of monoarthritis.
        J Pain. 2011; 12: 974-984
        • Montaner S.
        • Perona R.
        • Saniger L.
        • Lacal J.C.
        Multiple signalling pathways lead to the activation of the nuclear factor kappaB by the Rho family of GTPases.
        J Biol Chem. 1998; 273: 12779-12785
        • Moulin D.E.
        • Clark A.J.
        • Gilron I.
        • Ware M.A.
        • Watson C.P.
        • Sessle B.J.
        • Coderre T.
        • Morley-Forster P.K.
        • Stinson J.
        • Boulanger A.
        • Peng P.
        • Finley G.A.
        • Taenzer P.
        • Squire P.
        • Dion D.
        • Cholkan A.
        • Gilani A.
        • Gordon A.
        • Henry J.
        • Jovey R.
        • Lynch M.
        • Mailis-Gagnon A.
        • Panju A.
        • Rollman G.B.
        • Velly A.
        Pharmacological management of chronic neuropathic pain—Consensus statement and guidelines from the Canadian Pain Society.
        Pain Res Manag. 2007; 12: 13-21
        • Neary J.T.
        • Kang Y.
        • Willoughby K.A.
        • Ellis E.F.
        Activation of extracellular signal-regulated kinase by stretch-induced injury in astrocytes involves extracellular ATP and P2 purinergic receptors.
        J Neurosci. 2003; 23: 2348-2356
        • Paramore L.C.
        Use of alternative therapies: Estimates from the 1994 Robert Wood Johnson Foundation National Access to Care Survey.
        J Pain Symptom Manage. 1997; 13: 83-89
        • Randolph B.C.
        • Peters M.A.
        Analgesic effectiveness of ketorolac compared to meperidine in the rat formalin test.
        Anesth Prog. 1997; 44: 11-16
        • Schnabel A.
        • Poepping D.M.
        • Kranke P.
        • Zahn P.K.
        • Pogatzki-Zahn E.M.
        Efficacy and adverse effects of ketamine as an additive for paediatric caudal anaesthesia: A quantitative systematic review of randomized controlled trials.
        Br J Anaesth. 2011; 107: 601-611
        • Sun S.
        • Cao H.
        • Han M.
        • Li T.T.
        • Zhao Z.Q.
        • Zhang Y.Q.
        Evidence for suppression of electroacupuncture on spinal glial activation and behavioral hypersensitivity in a rat model of monoarthritis.
        Brain Res Bull. 2008; 75: 83-93
        • Tang J.S.
        • Qu C.L.
        • Huo F.Q.
        The thalamic nucleus submedius and ventrolateral orbital cortex are involved in nociceptive modulation: A novel pain modulation pathway.
        Prog Neurobiol. 2009; 89: 383-389
        • Thong T.
        • Colbert A.P.
        • Larsen A.P.
        An 8-channel skin impedance measurement system for acupuncture research.
        Conf Proc IEEE Eng Med Biol Soc. 2009; 2009: 861-864
        • Vercelino R.
        • Cunha T.M.
        • Ferreira E.S.
        • Cunha F.Q.
        • Ferreira S.H.
        • de Oliveira M.G.
        Skin vasodilation and analgesic effect of a topical nitric oxide-releasing hydrogel.
        J Mater Sci Mater Med. 2013; 24: 2157-2169
        • Vickers A.J.
        • Cronin A.M.
        • Maschino A.C.
        • Lewith G.
        • MacPherson H.
        • Foster N.E.
        • Sherman K.J.
        • Witt C.M.
        • Linde K.
        Acupuncture for chronic pain: Individual patient data meta-analysis.
        Arch Intern Med. 2012; 172: 1444-1453
        • Wang P.
        • Yang L.
        • You X.
        • Singh G.K.
        • Zhang L.
        • Yan Y.
        • Sung K.L.
        Mechanical stretch regulates the expression of matrix metalloproteinase in rheumatoid arthritis fibroblast-like synoviocytes.
        Connect Tissue Res. 2009; 50: 98-109
        • WHO Regional Office for the Western Pacific
        WHO Standard Acupuncture Point Locations in the Western Pacific Region.
        World Health Organization, Western Pacific Region, Manila2008
        • Woolf C.J.
        Central sensitization: implications for the diagnosis and treatment of pain.
        Pain. 2011; 152: 2-15
        • Woolf C.J.
        • Bennett G.J.
        • Doherty M.
        • Dubner R.
        • Kidd B.
        • Koltzenburg M.
        • Lipton R.
        • Loeser J.D.
        • Payne R.
        • Torebjork E.
        Towards a mechanism-based classification of pain?.
        Pain. 1998; 77: 227-229
        • Woollam C.H.
        • Jackson A.O.
        Acupuncture in the management of chronic pain.
        Anaesthesia. 1998; 53: 593-595
        • Xiong J.
        • Liu F.
        • Zhang M.M.
        • Wang W.
        • Huang G.Y.
        De-qi, not psychological factors, determines the therapeutic efficacy of acupuncture treatment for primary dysmenorrhea.
        Chin J Integr Med. 2011; 18: 7-15
        • Yang C.P.
        • Chang M.H.
        • Liu P.E.
        • Li T.C.
        • Hsieh C.L.
        • Hwang K.L.
        • Chang H.H.
        Acupuncture versus topiramate in chronic migraine prophylaxis: A randomized clinical trial.
        Cephalalgia. 2011; 31: 1510-1521
        • Zhao Z.Q.
        Neural mechanism underlying acupuncture analgesia.
        Prog Neurobiol. 2008; 85: 355-375
        • Zhou S.
        • Schmelz A.
        • Seufferlein T.
        • Li Y.
        • Zhao J.
        • Bachem M.G.
        Molecular mechanisms of low intensity pulsed ultrasound in human skin fibroblasts.
        J Biol Chem. 2004; 279: 54463-54469
        • Zijlstra F.J.
        • van den Berg-de Lange I.
        • Huygen F.J.
        • Klein J.
        Anti-inflammatory actions of acupuncture.
        Mediators Inflamm. 2003; 12: 59-69