title: Celastrol attenuates inflammatory and neuropathic pain mediated by cannabinoid receptor type 2.
abstract: Celastrol, a major active ingredient of Chinese herb Tripterygium wilfordii Hook. f. (thunder god vine), has exhibited a broad spectrum of pharmacological activities, including anti-inflammation, anti-cancer and immunosuppression. In the present study, we used animal models of inflammatory pain and neuropathic pain, generated by carrageenan injection and spared nerve injury (SNI), respectively, to evaluate the effect of celastrol and to address the mechanisms underlying pain processing. Intraperitoneal (i.p.) injection of celastrol produced a dose-dependent inhibition of carrageenan-induced edema and allodynia. Real-time PCR analysis showed that celastrol (0.3 mg/kg, i.p.) significantly reduced mRNA expressions of inflammatory cytokines, TNF-α, IL-6, IL-1β, in carrageenan-injected mice. In SNI mice, pain behavior studies showed that celastrol (1 mg/kg, i.p.) effectively prevented the hypersensitivity of mechanical nociceptive response on the third day post-surgery and the seventh day post-surgery. Furthermore, the anti-hyperalgesic effects of celastrol in carrageenan-injected mice and SNI mice were reversed by SR144528 (1 mg/kg, i.p.), a specific cannabinoid receptor-2 (CB2) receptor antagonist, but not by SR141716 (1 mg/kg, i.p.), a specific cannabinoid receptor-1 (CB1) receptor antagonist. Taken together, our results demonstrate the analgesia effects of celastrol through CB2 signaling and propose the potential of exploiting celastrol as a novel candidate for pain relief.
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen 361006, China. longhe.yang@gmail.com.
authors.forename: Longhe
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen 361006, China. 24520121153220@stu.xmu.edu.cn.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen 361006, China. renjie_7912@xmu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen 361006, China. chenggang.zhu@gmail.com.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen 361006, China. fujanie@gmail.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Fu
authors.affiliation: The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China. dhlin@xmu.edu.cn.
authors.forename: Donghai
authors.initials: D
authors.lastname: Lin
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen 361006, China. yanqiu@xmu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiu
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001892:Camphanes / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006930:Hyperalgesia / Q000188:drug therapy; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy*; D053978:Pentacyclic Triterpenes; D011720:Pyrazoles / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy; D029757:Tripterygium / Q000737:chemistry / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000700:Analgesics; D001892:Camphanes; D053583:Interleukin-1beta; D015850:Interleukin-6; D053978:Pentacyclic Triterpenes; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; C050414:celastrol
references.citation: Life Sci. 2013 Mar 19;92(8-9):498-505
references.pmid: 22749865
references.citation: ACS Chem Neurosci. 2012 May 16;3(5):356-63
references.pmid: 22860203
references.citation: Eur J Pharmacol. 2009 Jun 10;612(1-3):98-105
references.pmid: 19356734
references.citation: J Nat Prod. 2013 Nov 22;76(11):2060-4
references.pmid: 24175626
references.citation: Neuropharmacology. 2005 Apr;48(5):658-72
references.pmid: 15814101
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1755-60
references.pmid: 15665080
references.citation: Pain. 2006 May;122(1-2):14.e1-14
references.pmid: 16542774
references.citation: Br J Pharmacol. 2009 Feb;156(3):397-411
references.pmid: 19226257
references.citation: Br J Pharmacol. 2007 Mar;150(6):673-5
references.pmid: 17293886
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):243-56
references.pmid: 12052040
references.citation: PLoS One. 2013 Jun 17;8(6):e65477
references.pmid: 23799016
references.citation: Br J Pharmacol. 2013 Jun;169(4):808-19
references.pmid: 23043675
references.citation: Curr Opin Investig Drugs. 2008 Jan;9(1):65-75
references.pmid: 18183533
references.citation: Lancet Neurol. 2010 Aug;9(8):807-19
references.pmid: 20650402
references.citation: Cancer Lett. 2011 Apr 1;303(1):9-20
references.pmid: 21168266
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10529-33
references.pmid: 12917492
references.citation: J Pain. 2003 Oct;4(8):465-70
references.pmid: 14622667
references.citation: Chem Biol. 2009 Oct 30;16(10):1045-52
references.pmid: 19875078
references.citation: Br J Pharmacol. 2008 Jan;153(2):319-34
references.pmid: 17994113
references.citation: Prog Neurobiol. 2001 Apr;63(5):569-611
references.pmid: 11164622
references.citation: J Neuroinflammation. 2010 Mar 08;7:17
references.pmid: 20211007
references.citation: Curr Pharm Biotechnol. 2011 Oct;12(10):1644-59
references.pmid: 21466449
references.citation: J Biol Chem. 2012 Jun 22;287(26):22216-26
references.pmid: 22549786
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2001 Oct;25(7):1341-57
references.pmid: 11513350
references.citation: Neuropharmacology. 2012 Sep;63(4):593-605
references.pmid: 22613837
references.citation: BMJ. 2001 Jul 7;323(7303):13-6
references.pmid: 11440935
references.citation: Clin Exp Pharmacol Physiol. 2012 Mar;39(3):311-20
references.pmid: 21834865
references.citation: Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3300-11
references.pmid: 23108548
references.citation: Brain. 2003 Jun;126(Pt 6):1252-70
references.pmid: 12764049
references.citation: Adv Psychosom Med. 2011;30:125-138
references.pmid: 21508629
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9099-104
references.pmid: 18574142
references.citation: Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):133-44
references.pmid: 19285266
references.citation: Ann Rheum Dis. 2003 Apr;62(4):377-8
references.pmid: 12634249
references.citation: Neurotherapeutics. 2009 Oct;6(4):713-37
references.pmid: 19789075
references.citation: J Biol Chem. 2011 Apr 29;286(17):15138-46
references.pmid: 21402700