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Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis

Schuelert, Niklasa; Johnson, Michael P.b; Oskins, Jennifer L.c; Jassal, Karandeepa; Chambers, Mark G.c; McDougall, Jason J.a,*

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doi: 10.1016/j.pain.2010.11.025
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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 CB1 receptor antagonist AM251 (1 mg/kg intraperitoneally) or the CB2 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 CB1 antagonist abolished this effect. Local injection of URB597 into OA knee joints reduces mechanonociception and pain, and this response is mediated by CB1 receptors. Targeting endocannabinoid-metabolizing enzymes in the peripheral nervous system could offer novel therapeutic approaches for the treatment of OA pain.

Peripheral blockade of endocannabinoid hydrolysis reduced mechanonociception and pain in osteoarthritic knee joints.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

aDepartment of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1

bNeuroscience Discovery, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA

cMusculoskeletal Drug Hunting Team, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA

*Corresponding author. Address: Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Tel.: +1 403 220 4507; fax: +1 403 283 3840.

E-mail address:mcdougaj@ucalgary.ca

Article history: Received 13 February 2010; Received in revised form 10 November 2010; Accepted 22 November 2010.

© 2011 Lippincott Williams & Wilkins, Inc.
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