Fatty acid amide hydrolase inhibitor URB597 prevented tolerance and cognitive deficits induced by chronic morphine administration in rats.

Inhibitors of the endocannabinoid metabolic enzyme fatty acid amide hydrolase exert therapeutic effects, but might also be associated with some of the adverse effects of cannabis. However, at least one fatty acid amide hydrolase inhibitor, URB597, has beneficial effects without signs of abuse or dependence. Although previous investigations have evaluated URB597-morphine interactions, the effects of URB597 on morphine tolerance and cognition deficits have not been studied previously. Rats were rendered tolerant to or dependent on morphine by an injection of morphine (10 mg/kg, subcutaneous) twice daily, respectively, for 7 or 10 days. URB597 (1 mg/kg, intraperitoneal) was administered before morphine. The tail-flick and passive avoidance learning tests were used to evaluate tolerance and cognition. Chronic morphine injection led to significant tolerance to the antinociceptive effect on days 5 and 7. URB597 completely prevented the development of morphine tolerance. URB597 also enhanced memory acquisition in the passive avoidance learning test, and although morphine impaired memory, URB597 alleviated this effect. These data show that URB597 protects against tolerance and memory deficits in chronic usage of morphine and suggests URB597 as a promising candidate for the treatment of adverse effects of opioids.