Electroacupuncture induces antihyperalgesic effect through endothelin-B receptor in the chronic phase of a mouse model of complex regional pain syndrome type I
Complex regional pain syndrome (CRPS) is a disorder that involves abnormal inflammation and nerve dysfunction frequently resistant to a broad range of treatments. Peripheral nerve stimulation with electroacupuncture (EA) has been widely used in different clinical conditions to control pain and inflammation; however, the use of EA in the treatment of CRPS is under investigation. In this study, we explore the effects of EA on hyperalgesia and edema induced in an animal model of chronic post-ischemia pain (CPIP model) and the possible involvement of endothelin receptor type B (ETB) in this effect. Female Swiss mice were subjected to 3 h hind paw ischemia/reperfusion CPIP model. EA treatment produced time-dependent inhibition of mechanical and cold hyperalgesia, as well as edema in CPIP mice. Peripheral administration (i.pl.) of BQ-788 (10 nmol), an ETB antagonist, prevented EA-induced antihyperalgesia while intrathecal administration prolonged EA’s effect. Additionally, peripheral pre-treatment with sarafotoxin (SRTX S6c, 30 pmol, ETB agonist) increased EA anti-hyperalgesic effect. Furthermore, the expression of peripheral ETB receptors was increased after EA treatments, as measured by western blot. These results may suggest that EA’s analgesic effect is synergic with ETB receptor activation in the periphery, as well as central (spinal cord) ETB receptor blockade. These data support the use of EA as a nonpharmacological approach for the management of CRPS-I, in an adjuvant manner to ETB receptor targeting drugs.
KeywordsChronic pain Chronic post-ischemia pain Neuropathic pain Sanyinjiao (SP6) Zusanli (ST36)
Sources of funding
The present study was supported by grants from Universidade do Sul de Santa Catarina—Curso de Medicina and Programa Unisul de Iniciação Científica (PUIC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq - 476454/2013-1), and Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC-3414/2012), Brazil.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 3.Barrett KE, Barman SM, Boitano S, Heddwen LB (2014) Medical physiology of Ganong, 24th edn. Porto Alegre, AMGHGoogle Scholar
- 6.Coderre TJ, Xanthos DN, Francis L, Bennett GJ (2004) Chronic post-ischemia pain (CPIP) - a novel animal model of complex regional pain syndrome-type I (CRPS-I; reflex sympathetic dystrophy) produced by prolonged hindpaw ischemia and reperfusion in the rat. Pain 112:94–105CrossRefPubMedGoogle Scholar
- 15.Huang CP, Chen HN, Su HL, Hsieh CL, Chen WH, Lai ZR, Lin YW (2013) Electroacupuncture reduces carrageenan- and CFA-induced inflammatory pain accompanied by changing the expression of Nav1.7 and Nav1.8, rather than Nav1.9, in mice dorsal root ganglia. Evid based complement alternat med 1-8Google Scholar
- 19.Khodorova A, Navarro B, Jouaville LS, Murphy JE, Rice FL, Mazurkiewicz JE, Long-Woodward D, Stoffel M, Strichartz GR, Yukhananov R, Davar G (2003) Endothelin-B receptor activation triggers and endogenous analgesic cascade at sites of peripheral injury. Nat Med 9:1055–1061CrossRefPubMedGoogle Scholar
- 21.Kim HW, Uh DK, Yoon SY, Roh DH, Kwon YB, Han HJ, Lee HJ, Beitz AJ, Lee JH (2008) Low-frequency electroacupuncture suppresses carrageenan-induced paw inflammation in mice via sympathetic post-ganglionic neurons, while high-frequency EA suppression is mediated by the sympathoadrenal medullary axis. Brain Res Bull 75:698–705CrossRefPubMedGoogle Scholar
- 26.Liang Y, Fang JQ, Du JY, Fang JF (2012) Effect of electroacupuncture on activation of p38MAPK in spinal dorsal horn in rats with complete Freund’s adjuvant-induced inflammatory pain. Evid based complement Alternat Med 12:1–6Google Scholar
- 27.Martins DF, Emer AA, Batisti AP, Donatello N, Carlesso MG, Mazzardo-Martins L, Venzke D, Micke GA, Pizzolatti MG, Piovezan AP, dos Santos AR (2015) Inhalation of Cedrus atlantica essential oil alleviates pain behavior through activation of descending pain modulation pathways in a mouse model of postoperative pain. J Ethnopharmacol 175:30–38CrossRefPubMedGoogle Scholar
- 33.Moura D (2011) Use of infrared thermography in the analysis of horse thermoregulation in training. Eng Agric 31:23–32Google Scholar
- 40.Tian JH, Zhang W, Fang Y, Xu W, Grandy DK, Han JS (1998) Endogenous orphanin FQ: evidence for a role in the modulation of electroacupuncture analgesia and the development of tolerance to analgesia produced by morphine and electroacupuncture. Br J Pharmacol 124:21–26CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Treuting PM, Dintzis S (2011) Comparative anatomy and histology: a mouse and human atlas (expert consult), 1th ed. Academic PressGoogle Scholar