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.