title: Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors.
abstract: The in vivo effect of inhibitors of fatty acid amide hydrolase (FAAH) upon oedema volume and FAAH activity was evaluated in the carrageenan induced hind paw inflammation model in the mouse. Oedema was measured at two time points, 2 and 4 h, after intraplantar injection of carrageenan to anaesthetised mice. Intraperitoneal (i.p.) injections of the FAAH inhibitor URB597 (0.1, 0.3, 1 and 3 mg kg(-1)) 30 min prior to carrageenan administration, dose-dependently reduced oedema formation. At the 4 h time point, the ED(50) for URB597 was approximately 0.3 mg kg(-1). Indomethacin (5 mg kg(-1) i.p.) completely prevented the oedema response to carrageenan. The antioedema effects of indomethacin and URB597 were blocked by 3 mg kg(-1) i.p. of the CB(2) receptor antagonist SR144528. The effect of URB597 was not affected by pretreatment with the peroxisome proliferator-activated receptor gamma antagonist bisphenol A diglycidyl ether (30 mg kg(-1) i.p.) or the TRPV1 antagonist capsazepine (10 mg kg(-1) i.p.), when oedema was assessed 4 h after carrageenan administration. The CB(1) receptor antagonists AM251 (3 mg kg(-1) i.p.) and rimonabant (0.5 mg kg(-1) i.p.) gave inconsistent effects upon the antioedema effect of URB597. FAAH measurements were conducted ex vivo in the paws, spinal cords and brains of the mice. The activities of FAAH in the paws and spinal cords of the inflamed vehicle-treated mice were significantly lower than the corresponding activities in the noninflamed mice. PMSF treatment almost completely inhibited the FAAH activity in all three tissues, as did the highest dose of URB597 (3 mg kg(-1)) in spinal cord samples, whereas no obvious changes were seen ex vivo for the other treatments. In conclusion, the results show that in mice, treatment with indomethacin and URB597 produce SR144528-sensitive anti-inflammatory effects in the carrageenan model of acute inflammation.
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Sweden. Sandra.Holt@pharm.umu.se
authors.forename: Sandra
authors.initials: S
authors.lastname: Holt
authors.forename: Francesca
authors.initials: F
authors.lastname: Comelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D001921:Brain / Q000201:enzymology; D001892:Camphanes / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates / Q000627:therapeutic use*; D002351:Carrageenan; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006614:Hindlimb / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007213:Indomethacin / Q000627:therapeutic use*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010424:Pentobarbital / Q000494:pharmacology; D010664:Phenylmethylsulfonyl Fluoride / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology; D013116:Spinal Cord / Q000201:enzymology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D001892:Camphanes; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D002351:Carrageenan; D004791:Enzyme Inhibitors; D007213:Indomethacin; D010424:Pentobarbital; D010664:Phenylmethylsulfonyl Fluoride; D011720:Pyrazoles; D000099252:Fatty Acid Amide Hydrolases; C110630:SR 144528; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester