Delta(9)-tetrahydrocannabinol releases and facilitates the effects of endogenous enkephalins: reduction in morphine withdrawal syndrome without change in rewarding effect

Recent studies have suggested that cannabinoids might initiate the consumpt ion of other highly addictive substances, such as opiates. In this work, we show that acute administration of Delta (9)-tetrahydrocannabinol in mice f acilitates the antinociceptive and antidepressant-like responses elicited b y the endogenous enkephalins protected from their degradation by RB 101, a complete inhibitor of enkephalin catabolism. This emphasizes the existence of a physiological interaction between endogenous opioid and cannabinoid sy stems. Accordingly, Delta (9)-tetrahydrocannabinol increased the release of Met-enkephalin-like material in the nucleus accumbens of awake and freely moving rats measured by microdialysis. In addition, this cannabinoid agonis t displaced the in vivo [H-3]diprenorphine binding to opioid receptors in t otal mouse brain. The repetitive pretreatment during 3 weeks of Delta (9)-t etrahydrocannabinol in mice treated chronically with morphine significantly reduces the naloxone-induced withdrawal syndrome. However, this repetitive administration of Delta (9)-tetrahydrocannabinol did not modify or even de crease the rewarding responses produced by morphine in the place preference paradigm. Taken together, these behavioural and biochemical results demons trate the existence of a direct link between endogenous opioid and cannabin oid systems. However, chronic use of high doses of cannabinoids does not se em to potentiate the psychic dependence to opioids.