Correlation between the in vivo and an in vitro expression of opiate withdrawal precipitated by naloxone: their antagonism by l-(-)-delta9-tetrahydrocannabinol

Abstract

Guinea pigs treated with a single s.c. injection of a slowly released morphine suspension (300 mg/kg) exhibited a quantifiable withdrawal syndrome after naloxone injection (0.01-10 mg/kg s.c.). Ileum removed from such animals responded to naloxone (1-300 ng/ml) by contracting. These contractions could be blocked by scopolamine or tetrodotoxin. Both the in vivo and in vitro responses were specific for the opiate-dependent state and were dependent on naloxone dose. Time courses of the development and decline of the two responses were similar. Weaker opioids, pentazocine and codeine, were less effective than morphine in producing a dependent state and sensitizing ileum to naloxone. 1-(-)-delta9-Tetrahydrocann abinol [1-(-)-delta9-THC] antagonized the effect of naloxone on ileum without affecting responses to acetylcholine. 1-(-)-delta9-THC produced a stereospecific, dose-dependent (1-10 mg/kg p.o.) inhibition of naloxone-precipitated withdrawal in guinea pigs and rats that was more complete than and different from that produced by sedatives. Pentobarbital inhibited withdrawal only at doses that produced ataxia. 1-(-)-delta9-THC had a biphasic effect on locomotor activity of guinea pig in the dose range that inhibited withdrawal, stimulation at 1 mg/kg and depression at 3 to 10 mg/kg. Our results suggest that cannabinoids may be useful in opiate detoxification. The inhibition by 1-(-)-delta9-THC of the action of naloxone in "dependent" ileum seems to be via reduction in acetylcholine release. Whereas the end result of 1-(-)-delta9-THC action in brain may not necessarily be a reduction in acetylcholine release as in ileum, the mechanism by which it produces this effect in the ileum model may explain its ability to antagonize withdrawal.