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.