title: The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice.
abstract: Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1-50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB(1) receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB(2) antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.
authors.affiliation: Department of Experimental Pharmacology, University of Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.forename: Jesse
authors.initials: J
authors.lastname: Loverme
authors.forename: Giovanna
authors.initials: G
authors.lastname: La Rana
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Compton
authors.forename: Jeff
authors.initials: J
authors.lastname: Parrott
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tontini
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000284:Administration, Oral; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D051379:Mice; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000502:physiology; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D001549:Benzamides; D002219:Carbamates; D004791:Enzyme Inhibitors; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester