title: Peripheral FAAH inhibition causes profound antinociception and protects against indomethacin-induced gastric lesions.
abstract: Fatty-acid amide hydrolase (FAAH) catalyzes the intracellular hydrolysis of the endocannabinoid anandamide and other bioactive lipid amides. In the present study, we conducted a comparative characterization of the effects of the newly identified brain-impermeant FAAH inhibitor, URB937 ([3-(3-carbamoylphenyl)-4-hydroxy-phenyl] N-cyclohexylcarbamate), in various rodent models of acute and persistent pain. When administered by the oral route in mice, URB937 was highly active (median effective dose, ED(50), to inhibit liver FAAH activity: 0.3mgkg(-1)) and had a bioavailability of 5.3%. The antinociceptive effects of oral URB937 were investigated in mouse models of acute inflammation (carrageenan), peripheral nerve injury (chronic sciatic nerve ligation) and arthritis (complete Freund's adjuvant). In all models, URB937 was as effective or more effective than standard analgesic and anti-inflammatory drugs (indomethacin, gabapentin, dexamethasone) and reversed pain-related responses (mechanical hyperalgesia, thermal hyperalgesia, and mechanical allodynia) in a dose-dependent manner. ED(50) values ranged from 0.2 to 10mgkg(-1), depending on model and readout. Importantly, URB937 was significantly more effective than two global FAAH inhibitors, URB597 and PF-04457845, in the complete Freund's adjuvant model. The effects of a combination of URB937 with the non-steroidal anti-inflammatory agent, indomethacin, were examined in the carrageenan and chronic sciatic nerve ligation models. Isobolographic analyses showed that the two compounds interacted synergistically to attenuate pain-related behaviors. Furthermore, URB937 reduced the number and severity of gastric lesions produced by indomethacin, while exerting no ulcerogenic effect when administered alone. The results indicate that the peripheral FAAH inhibitor URB937 is more effective than globally active FAAH inhibitors at inhibiting inflammatory pain. Our findings further suggest that FAAH and cyclooxygenase inhibitors interact functionally in peripheral tissues, to either enhance or hinder each other's actions.
authors.affiliation: Drug Discovery and Development, Italian Institute of Technology, Via Morego, 30, Genova 16163, Italy.
authors.forename: Oscar
authors.initials: O
authors.lastname: Sasso
authors.forename: Rosalia
authors.initials: R
authors.lastname: Bertorelli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Giampiero
authors.initials: G
authors.lastname: Colombano
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.forename: Guillermo
authors.initials: G
authors.lastname: Moreno-Sanz
authors.forename: Angelo
authors.initials: A
authors.lastname: Reggiani
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000633:toxicity; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology; D002186:Cannabinoids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007213:Indomethacin / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D011724:Pyridazines / Q000494:pharmacology; D012584:Sciatic Nerve / Q000293:injuries / Q000503:physiopathology; D013276:Stomach Ulcer / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D002186:Cannabinoids; D002219:Carbamates; D004791:Enzyme Inhibitors; D007213:Indomethacin; D011724:Pyridazines; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C560620:N-pyridazin-3-yl-4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxamide; C552918:URB937; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester