title: Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis.
abstract: The present study examined whether enhancement of endogenous cannabinoid levels by administration of the fatty acid amide hydrolase inhibitor URB597 could modulate joint nociception in 2 rodent models of osteoarthritis (OA). OA-like changes were induced in male Wistar rats by intra-articular injection of monoiodoacetate, while Dunkin-Hartley guinea pigs (age 9-12 months) develop OA naturally and were used as a model of spontaneous OA. Joint nociception was measured by recording electrophysiologically from knee joint primary afferents in response to noxious hyper-rotation of the joint before and after close intra-arterial injection of URB597 (0.03 mg; 0.1 mL bolus); the CB(1) receptor antagonist AM251 (1 mg/kg intraperitoneally) or the CB(2) receptor antagonist AM630 (1 mg/kg intraperitoneally). The effect of systemic URB597 administration (5 mg/kg) on joint pain perception in the monoiodoacetate model was determined by hindlimb incapacitance. Peripheral injection of URB597 caused afferent firing rate to be significantly reduced by up to 56% in the rat OA model and by up to 69% in the guinea pig OA model. Systemic co-administration of AM251, but not AM630, abolished the antinociceptive effect of URB597 in both models. URB597 had no effect in saline-injected control rat joints or in nonarthritic guinea pigs. Systemic URB597 administration significantly reduced hindlimb incapacitance in monoiodoacetate joints and co-administration of the CB(1) antagonist abolished this effect. Local injection of URB597 into OA knee joints reduces mechanonociception and pain, and this response is mediated by CB(1) receptors. Targeting endocannabinoid-metabolizing enzymes in the peripheral nervous system could offer novel therapeutic approaches for the treatment of OA pain.
authors.affiliation: Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1 Neuroscience Discovery, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA Musculoskeletal Drug Hunting Team, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Schuelert
authors.forename: Michael P
authors.initials: MP
authors.lastname: Johnson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Oskins
authors.forename: Karandeep
authors.initials: K
authors.lastname: Jassal
authors.forename: Mark G
authors.initials: MG
authors.lastname: Chambers
authors.forename: Jason J
authors.initials: JJ
authors.lastname: McDougall
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000344:Afferent Pathways / Q000166:cytology / Q000187:drug effects; D000367:Age Factors; D000818:Animals; D018771:Arthralgia / Q000188:drug therapy* / Q000209:etiology*; D001549:Benzamides / Q000627:therapeutic use*; D002219:Carbamates / Q000627:therapeutic use*; D004008:Diclofenac / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006168:Guinea Pigs; D007211:Indoles / Q000627:therapeutic use; D019807:Iodoacetic Acid / Q000009:adverse effects*; D008297:Male; D009619:Nociceptors / Q000187:drug effects; D010003:Osteoarthritis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D016474:Weight-Bearing
chemical_list: D001549:Benzamides; D002219:Carbamates; D004791:Enzyme Inhibitors; D007211:Indoles; D010880:Piperidines; D011720:Pyrazoles; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D004008:Diclofenac; C103505:AM 251; C094023:iodopravadoline; D019807:Iodoacetic Acid