A potent and selective inhibitor of endocannabinoid uptake, UCM707, potentiates antinociception induced by cholestasis

Cholestasis is associated with changes including analgesia. The endocannabinoid system can reduce pain sensitivity. Considering the interaction between the endogenous opioid and endocannabinoid systems in nociception processing, we studied the effect of UCM707 as a potent and selective inhibitor of endocannabinoid uptake on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis. Cholestasis was induced in male Sprague-Dawley rats by ligation of the main bile duct using two ligatures and transecting the duct at the midpoint between them. Seven days later, tail-flick latencies were measured 10 min after injection of UCM707 (0.1, 1 and 10 mg/kg, i.p.) alone or with co-administration of a CB(1) receptor antagonist, AM251 (1 mg/kg, i.p.), with UCM707 (10 mg/kg, i.p.) in experimental groups. A significant increase (P < 0.01) in tail-flick latency was observed in cholestatic rats compared with rats belonging to unoperated and sham groups. Administration of UCM707 (1 and 10 mg/kg) to cholestatic animals significantly increased tail-flick latency compared with the vehicle-treated cholestatic group (P < 0.05 and P < 0.001, respectively). UCM707 injection in unoperated and sham groups did not alter baseline tail-flick latency compared with vehicle-treated groups. The effect of UCM707 in the cholestatic group was blocked by co-administration of AM251 (1 mg/kg, i.p.) with UCM707. These data showed that the endocannabinoid system is involved in nociception processing during cholestasis and that the effects of UCM707 on the pain threshold in cholestatic rats may be a result of CB(1) receptor activation by the increased extracellular levels of endocannabinoids.