Top

Molecular Pain

Published in:

Open Access 01-12-2011 | Research

Cannabinoid CB2 Receptors Contribute to Upregulation of β-endorphin in Inflamed Skin Tissues by Electroacupuncture

Authors: Tang-feng Su, Ling-hong Zhang, Miao Peng, Cai-hua Wu, Wen Pan, Bo Tian, Jing Shi, Hui-lin Pan, Man Li

Published in: Molecular Pain | Issue 1/2011

Abstract

Background

Electroacupuncture (EA) can produce analgesia by increasing the β-endorphin level and activation of peripheral μ-opioid receptors in inflamed tissues. Endogenous cannabinoids and peripheral cannabinoid CB2 receptors (CB2Rs) are also involved in the antinociceptive effect of EA on inflammatory pain. However, little is known about how peripheral CB2Rs interact with the endogenous opioid system at the inflammatory site and how this interaction contributes to the antinociceptive effect of EA on inflammatory pain. In this study, we determined the role of peripheral CB2Rs in the effects of EA on the expression of β-endorphin in inflamed skin tissues and inflammatory pain.

Results

Inflammatory pain was induced by injection of complete Freund's adjuvant into the left hindpaw of rats. Thermal hyperalgesia was tested with a radiant heat stimulus, and mechanical allodynia was quantified using von Frey filaments. The mRNA level of POMC and protein level of β-endorphin were quantified by real-time PCR and Western blotting, respectively. The β-endorphin-containing keratinocytes and immune cells in the inflamed skin tissues were detected by double-immunofluorescence labeling. The CB2R agonist AM1241 or EA significantly reduced thermal hyperalgesia and mechanical allodynia, whereas the selective μ-opioid receptor antagonist β-funaltrexamine significantly attenuated the antinociceptive effect produced by them. AM1241 or EA significantly increased the mRNA level of POMC and the protein level of β-endorphin in inflamed skin tissues, and these effects were significantly attenuated by pretreatment with the CB2R antagonist AM630. AM1241 or EA also significantly increased the percentage of β-endorphin-immunoreactive keratinocytes, macrophages, and T-lymphocytes in inflamed skin tissues, and these effects were blocked by AM630.

Conclusions

EA and CB2R stimulation reduce inflammatory pain through activation of μ-opioid receptors. EA increases endogenous opioid expression in keratinocytes and infiltrating immune cells at the inflammatory site through CB2R activation.

Available only for authorised users

Kuai L, Yang H, Liu T, Gao M: Quantitative research on effects of electroacupuncture on different parameters on analgesia in rats with adjuvant-induced arthritis. Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering 2007, 24: 186–190.PubMed

Taguchi R, Taguchi T, Kitakoji H: Involvement of peripheral opioid receptors in electroacupuncture analgesia for carrageenan-induced hyperalgesia. Brain research 2010, 1355: 97–103.PubMedCrossRef

Sekido R, Ishimaru K, Sakita M: Differences of electroacupuncture-induced analgesic effect in normal and inflammatory conditions in rats. Am J Chin Med 2003, 31: 955–965. 10.1142/S0192415X03001491PubMedCrossRef

Chen L, Zhang J, Li F, Qiu Y, Wang L, Li YH, Shi J, Pan HL, Li M: Endogenous anandamide and cannabinoid receptor-2 contribute to electroacupuncture analgesia in rats. J Pain 2009, 10: 732–739. 10.1016/j.jpain.2008.12.012PubMedCrossRef

Zhang J, Chen L, Su T, Cao F, Meng X, Pei L, Shi J, Pan HL, Li M: Electroacupuncture increases CB2 receptor expression on keratinocytes and infiltrating inflammatory cells in inflamed skin tissues of rats. J Pain 2010, 11: 1250–1258. 10.1016/j.jpain.2010.02.013PubMedCrossRef

Cabot PJ, Carter L, Gaiddon C, Zhang Q, Schafer M, Loeffler JP, Stein C: Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats. The Journal of clinical investigation 1997, 100: 142–148. 10.1172/JCI119506PubMedCentralPubMedCrossRef

Cabot PJ, Carter L, Schafer M, Stein C: Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain. Pain 2001, 93: 207–212. 10.1016/S0304-3959(01)00322-0PubMedCrossRef

Labuz D, Berger S, Mousa SA, Zollner C, Rittner HL, Shaqura MA, Segovia-Silvestre T, Przewlocka B, Stein C, Machelska H: Peripheral antinociceptive effects of exogenous and immune cell-derived endomorphins in prolonged inflammatory pain. J Neurosci 2006, 26: 4350–4358. 10.1523/JNEUROSCI.4349-05.2006PubMedCrossRef

Zhang RX, Lao L, Wang L, Liu B, Wang X, Ren K, Berman BM: Involvement of opioid receptors in electroacupuncture-produced anti-hyperalgesia in rats with peripheral inflammation. Brain research 2004, 1020: 12–17. 10.1016/j.brainres.2004.05.067PubMedCrossRef

10.

van der Merwe PA, Davis SJ: Molecular interactions mediating T cell antigen recognition. Annual review of immunology 2003, 21: 659–684. 10.1146/annurev.immunol.21.120601.141036PubMedCrossRef

11.

Stein C, Hassan AH, Przewlocki R, Gramsch C, Peter K, Herz A: Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proceedings of the National Academy of Sciences of the United States of America 1990, 87: 5935–5939. 10.1073/pnas.87.15.5935PubMedCentralPubMedCrossRef

12.

Przewlocki R, Hassan AH, Lason W, Epplen C, Herz A, Stein C: Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception. Neuroscience 1992, 48: 491–500. 10.1016/0306-4522(92)90509-ZPubMedCrossRef

13.

Coggeshall RE, Zhou S, Carlton SM: Opioid receptors on peripheral sensory axons. Brain research 1997, 764: 126–132. 10.1016/S0006-8993(97)00446-0PubMedCrossRef

14.

Mousa SA, Zhang Q, Sitte N, Ji R, Stein C: beta-Endorphin-containing memory-cells and mu-opioid receptors undergo transport to peripheral inflamed tissue. Journal of neuroimmunology 2001, 115: 71–78. 10.1016/S0165-5728(01)00271-5PubMedCrossRef

15.

Hohmann AG, Herkenham M: Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neuroscience 1999, 90: 923–931. 10.1016/S0306-4522(98)00524-7PubMedCrossRef

16.

Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993, 365: 61–65. 10.1038/365061a0PubMedCrossRef

17.

Quartilho A, Mata HP, Ibrahim MM, Vanderah TW, Porreca F, Makriyannis A, Malan TP Jr: Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology 2003, 99: 955–960. 10.1097/00000542-200310000-00031PubMedCrossRef

18.

Yao BB, Hsieh GC, Frost JM, Fan Y, Garrison TR, Daza AV, Grayson GK, Zhu CZ, Pai M, Chandran P, Salyers AK, Wensink EJ, Honore P, Sullivan JP, Dart MJ, Meyer MD: In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models. Br J Pharmacol 2008, 153: 390–401. 10.1038/sj.bjp.0707568PubMedCentralPubMedCrossRef

19.

Ward SJ, Portoghese PS, Takemori AE: Pharmacological characterization in vivo of the novel opiate, beta-funaltrexamine. The Journal of pharmacology and experimental therapeutics 1982, 220: 494–498.PubMed

20.

Smith EM: Opioid peptides in immune cells. Adv Exp Med Biol 2003, 521: 51–68.PubMed

21.

Sitte N, Busch M, Mousa SA, Labuz D, Rittner H, Gore C, Krause H, Stein C, Schafer M: Lymphocytes upregulate signal sequence-encoding proopiomelanocortin mRNA and beta-endorphin during painful inflammation in vivo. Journal of neuroimmunology 2007, 183: 133–145. 10.1016/j.jneuroim.2006.11.033PubMedCrossRef

22.

Mousa SA, Shakibaei M, Sitte N, Schafer M, Stein C: Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain. Endocrinology 2004, 145: 1331–1341.PubMedCrossRef

23.

Funasaka Y, Chakraborty AK, Yodoi J, Ichihashi M: The effect of thioredoxin on the expression of proopiomelanocortin-derived peptides, the melanocortin 1 receptor and cell survival of normal human keratinocytes. J Investig Dermatol Symp Proc 2001, 6: 32–37. 10.1046/j.0022-202x.2001.00002.xPubMedCrossRef

24.

Wintzen M, Yaar M, Burbach JP, Gilchrest BA: Proopiomelanocortin gene product regulation in keratinocytes. J Invest Dermatol 1996, 106: 673–678. 10.1111/1523-1747.ep12345496PubMedCrossRef

25.

Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, Davar G, Makriyannis A, Vanderah TW, Mata HP, Malan TP Jr: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proceedings of the National Academy of Sciences of the United States of America 2005, 102: 3093–3098. 10.1073/pnas.0409888102PubMedCentralPubMedCrossRef

26.

Stein C, Schafer M, Machelska H: Attacking pain at its source: new perspectives on opioids. Nat Med 2003, 9: 1003–1008. 10.1038/nm908PubMedCrossRef

27.

Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrie B, Rinaldi-Carmona M, Calandra B, Le Fur G, Casellas P: Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. European journal of biochemistry/FEBS 1996, 237: 704–711. 10.1111/j.1432-1033.1996.0704p.xPubMedCrossRef

28.

Kobayashi Y, Arai S, Waku K, Sugiura T: Activation by 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, of p42/44 mitogen-activated protein kinase in HL-60 cells. Journal of biochemistry 2001, 129: 665–669. 10.1093/oxfordjournals.jbchem.a002904PubMedCrossRef

29.

Derocq JM, Jbilo O, Bouaboula M, Segui M, Clere C, Casellas P: Genomic and functional changes induced by the activation of the peripheral cannabinoid receptor CB2 in the promyelocytic cells HL-60. Possible involvement of the CB2 receptor in cell differentiation. The Journal of biological chemistry 2000, 275: 15621–15628. 10.1074/jbc.275.21.15621PubMedCrossRef

30.

Ballet S, Conrath M, Fischer J, Kaneko T, Hamon M, Cesselin F: Expression and G-protein coupling of mu-opioid receptors in the spinal cord and dorsal root ganglia of polyarthritic rats. Neuropeptides 2003, 37: 211–219. 10.1016/S0143-4179(03)00045-3PubMedCrossRef

31.

Truong W, Cheng C, Xu QG, Li XQ, Zochodne DW: Mu opioid receptors and analgesia at the site of a peripheral nerve injury. Annals of neurology 2003, 53: 366–375. 10.1002/ana.10465PubMedCrossRef

32.

Puehler W, Zollner C, Brack A, Shaqura MA, Krause H, Schafer M, Stein C: Rapid upregulation of mu opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation depends on neuronal conduction. Neuroscience 2004, 129: 473–479. 10.1016/j.neuroscience.2004.06.086PubMedCrossRef

33.

Fernandez-Duenas V, Pol O, Garcia-Nogales P, Hernandez L, Planas E, Puig MM: Tolerance to the antinociceptive and antiexudative effects of morphine in a murine model of peripheral inflammation. The Journal of pharmacology and experimental therapeutics 2007, 322: 360–368. 10.1124/jpet.106.118901PubMedCrossRef

34.

Rittner HL, Brack A, Machelska H, Mousa SA, Bauer M, Schafer M, Stein C: Opioid peptide-expressing leukocytes: identification, recruitment, and simultaneously increasing inhibition of inflammatory pain. Anesthesiology 2001, 95: 500–508. 10.1097/00000542-200108000-00036PubMedCrossRef

35.

Bigliardi-Qi M, Sumanovski LT, Buchner S, Rufli T, Bigliardi PL: Mu-opiate receptor and Beta-endorphin expression in nerve endings and keratinocytes in human skin. Dermatology 2004, 209: 183–189. 10.1159/000079887PubMedCrossRef

36.

Khodorova A, Navarro B, Jouaville LS, Murphy JE, Rice FL, Mazurkiewicz JE, Long-Woodward D, Stoffel M, Strichartz GR, Yukhananov R, Davar G: Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat Med 2003, 9: 1055–1061. 10.1038/nm885PubMedCrossRef

37.

Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983, 16: 109–110. 10.1016/0304-3959(83)90201-4PubMedCrossRef

38.

Cook CD, Moore KI: Effects of sex, hindpaw injection site and stimulus modality on nociceptive sensitivity in arthritic rats. Physiol Behav 2006, 87: 552–562. 10.1016/j.physbeh.2005.12.005PubMedCrossRef

39.

Yung KT: Birdcage model for the Chinese meridian system: part VI. meridians as the primary regulatory system. Am J Chin Med 2005, 33: 759–766. 10.1142/S0192415X05003302PubMedCrossRef

40.

Wang L, Zhang Y, Dai J, Yang J, Gang S: Electroacupuncture (EA) modulates the expression of NMDA receptors in primary sensory neurons in relation to hyperalgesia in rats. Brain research 2006, 1120: 46–53. 10.1016/j.brainres.2006.08.077PubMedCrossRef

41.

Malan TP, Ibrahim MM, Deng H, Liu Q, Mata HP, Vanderah T, Porreca F, Makriyannis A: CB2 cannabinoid receptor-mediated peripheral antinociception. Pain 2001, 93: 239–245. 10.1016/S0304-3959(01)00321-9PubMedCrossRef

42.

Ross RA, Brockie HC, Stevenson LA, Murphy VL, Templeton F, Makriyannis A, Pertwee RG: Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630. Br J Pharmacol 1999, 126: 665–672. 10.1038/sj.bjp.0702351PubMedCentralPubMedCrossRef

43.

Correa JD, Paiva-Lima P, Rezende RM, Dos Reis WG, Ferreira-Alves DL, Bakhle YS, Francischi JN: Peripheral mu-, kappa- and delta-opioid receptors mediate the hypoalgesic effect of celecoxib in a rat model of thermal hyperalgesia. Life sciences 2010, 86: 951–956. 10.1016/j.lfs.2010.04.012PubMedCrossRef

44.

Hargreaves K, Dubner R, Brown F, Flores C, Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988, 32: 77–88. 10.1016/0304-3959(88)90026-7PubMedCrossRef

45.

Schagger H: Tricine-SDS-PAGE. Nat Protoc 2006, 1: 16–22. 10.1038/nprot.2006.4PubMedCrossRef

46.

Liu H, Li H, Guo L, Li C, Li M, Jiang W, Liu X, McNutt MA, Li G: The mechanism involved in the repression of the mu opioid receptor gene expression in CEM x174 cells infected by simian immunodeficiency virus. Journal of leukocyte biology 2009, 85: 684–691. 10.1189/jlb.0908543PubMedCrossRef

47.

Kivell BM, Day DJ, McDonald FJ, Miller JH: Developmental expression of mu and delta opioid receptors in the rat brainstem: evidence for a postnatal switch in mu isoform expression. Brain Res Dev Brain Res 2004, 148: 185–196.PubMedCrossRef

48.

Lane EB, Rugg EL, Navsaria H, Leigh IM, Heagerty AH, Ishida-Yamamoto A, Eady RA: A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature 1992, 356: 244–246. 10.1038/356244a0PubMedCrossRef

49.

Damoiseaux JG, Dopp EA, Calame W, Chao D, MacPherson GG, Dijkstra CD: Rat macrophage lysosomal membrane antigen recognized by monoclonal antibody ED1. Immunology 1994, 83: 140–147.PubMedCentralPubMed

50.

Hunig T, Wallny HJ, Hartley JK, Lawetzky A, Tiefenthaler G: A monoclonal antibody to a constant determinant of the rat T cell antigen receptor that induces T cell activation. Differential reactivity with subsets of immature and mature T lymphocytes. J Exp Med 1989, 169: 73–86. 10.1084/jem.169.1.73PubMedCrossRef

Title: Cannabinoid CB2 Receptors Contribute to Upregulation of β-endorphin in Inflamed Skin Tissues by Electroacupuncture
Authors: Tang-feng Su
Ling-hong Zhang
Miao Peng
Cai-hua Wu
Wen Pan
Bo Tian
Jing Shi
Hui-lin Pan
Man Li
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2011
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-7-98

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Cannabinoid CB2 Receptors Contribute to Upregulation of β-endorphin in Inflamed Skin Tissues by Electroacupuncture

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2011

Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation

Expression of the dopaminergic D1 and D2 receptors in the anterior cingulate cortex in a model of neuropathic pain

Identification of sodium channel isoforms that mediate action potential firing in lamina I/II spinal cord neurons

Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy

Accumulation of Kv7.2 channels in putative ectopic transduction zones of mice nerve-end neuromas

PAP and NT5E inhibit nociceptive neurotransmission by rapidly hydrolyzing nucleotides to adenosine