title: The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation.
abstract: OBJECTIVE
  2-arachidonoylglycerol (2-AG) is an endocannabinoid whose hydrolysis is predominantly catalysed by the enzyme monoacylglycerol lipase (MAGL). The development of MAGL inhibitors could offer an opportunity to investigate the anti-inflammatory and anti-nociceptive role of 2-AG, which have not yet been elucidated. On these bases, URB602, a MAGL inhibitor, was tested in a murine model of inflammation/inflammatory pain.
  
  
  METHODS
  Acute inflammation was induced by intraplantar injection of lambda-carrageenan into mice. The highest dose to be employed has been selected performing the tetrad assays for cannabimimetic activity in mice. URB602 anti-inflammatory and anti-nociceptive efficacy (assessed by plethysmometer and plantar test, respectively) was evaluated both in a preventive regimen (drug administered 30 min before carrageenan) and in a therapeutic regimen (URB602 administered 30 min after carrageenan). To elucidate the cannabinoid receptor involvement, rimonabant and SR144528, CB1 and CB2 selective antagonists, respectively, were given 15 min before URB602.
  
  
  RESULTS
  Systemic administration of URB602 elicited a dose-dependent anti-oedemigen and anti-nociceptive effect that was reversed exclusively by the CB2 receptor antagonist. The efficacy of URB602 persisted also when the compound was administered in a therapeutic regimen, suggesting the ability of URB602 to improve established disease.
  
  
  CONCLUSIONS
  The present report highlighted the ability of the selective MAGL inhibitor, URB602, to prevent and treat an acute inflammatory disease without producing adverse psychoactive effects. The data presented herein also contributed to clarify the physiological role of 2-AG in respect to inflammatory reactions, suggesting its protective role in the body.
authors: Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milano, Italy.
authors: F
authors: F
authors: Comelli
authors: G
authors: G
authors: Giagnoni
authors: I
authors: I
authors: Bettoni
authors: M
authors: M
authors: Colleoni
authors: B
authors: B
authors: Costa
mesh_terms: D000208:Acute Disease; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D001892:Camphanes / Q000494:pharmacology; D002351:Carrageenan / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D006614:Hindlimb; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D000077285:Rimonabant
chemical_list: D001713:Biphenyl Compounds; D001892:Camphanes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; C501835:URB602; D002351:Carrageenan; D008994:Monoacylglycerol Lipases; D000077285:Rimonabant
references: Glia. 2003 Jan 15;41(2):161-8
references: 12509806
references: Chem Phys Lipids. 2002 Dec 31;121(1-2):149-58
references: 12505697
references: Br J Pharmacol. 1972 Dec;46(4):753-63
references: 4655271
references: Pain. 1983 Jun;16(2):109-10
references: 6877845
references: Pain. 1988 Jan;32(1):77-88
references: 3340425
references: Science. 1992 Dec 18;258(5090):1946-9
references: 1470919
references: J Pharmacol Exp Ther. 1993 Apr;265(1):218-26
references: 8474008
references: Biochem Pharmacol. 1995 Jun 29;50(1):83-90
references: 7605349
references: Biochem Biophys Res Commun. 1995 Oct 4;215(1):89-97
references: 7575630
references: Nature. 1997 Aug 21;388(6644):773-8
references: 9285589
references: J Pharmacol Exp Ther. 1998 Feb;284(2):644-50
references: 9454810
references: Biochem J. 1998 Apr 1;331 ( Pt 1):15-9
references: 9512456
references: Mol Pharmacol. 1998 Apr;53(4):676-83
references: 9547358
references: J Biol Chem. 1999 Jan 29;274(5):2794-801
references: 9915812
references: J Biol Chem. 2005 May 6;280(18):18488-97
references: 15749716
references: Pharmacol Biochem Behav. 2005 Jun;81(2):224-38
references: 15935454
references: Nature. 2005 Jun 23;435(7045):1108-12
references: 15973410
references: Nat Neurosci. 2005 Sep;8(9):1139-41
references: 16116451
references: Behav Pharmacol. 2005 Sep;16(5-6):363-72
references: 16148440
references: Br J Pharmacol. 2005 Oct;146(3):467-76
references: 16100529
references: Neuropharmacology. 2006 Mar;50(3):372-9
references: 16316669
references: Eur J Pharmacol. 2006 May 24;538(1-3):154-62
references: 16647054
references: J Neurosci. 2007 Mar 14;27(11):2883-9
references: 17360910
references: Br J Pharmacol. 2007 Mar;150(6):693-701
references: 17179944
references: Eur J Pharmacol. 2007 Aug 13;569(1-2):70-6
references: 17553486
references: Eur J Pharmacol. 1999 Nov 19;384(2-3):153-6
references: 10611435
references: J Biol Chem. 2000 Jan 7;275(1):605-12
references: 10617657
references: Mol Pharmacol. 2000 May;57(5):1045-50
references: 10779390
references: Eur J Pharmacol. 2000 Oct 6;406(1):R5-7
references: 11011050
references: Br J Pharmacol. 2001 Oct;134(3):664-72
references: 11588122
references: Eur J Pharmacol. 2001 Nov 30;432(1):107-19
references: 11734194
references: J Biol Chem. 2002 Jan 18;277(3):1816-23
references: 11682480
references: Pharmacol Biochem Behav. 2002 Nov;73(4):911-9
references: 12213538
references: Mol Pharmacol. 2004 Nov;66(5):1260-4
references: 15272052