CORRELATION BETWEEN INVIVO AND AN INVITRO EXPRESSION OF OPIATE WITHDRAWAL PRECIPITATED BY NALOXONE - THEIR ANTAGONISM BY L-(-)-DELTA9-TETRAHYDROCANNABINOL

  • 1 January 1976
    • journal article
    • research article
    • Vol. 199  (2) , 375-384
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/k 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. 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 2 responses were similar. Weaker opioids, pentazocine and codeine, were less effective than morphine in producing a dependent state and sensitizing ileum to naloxone. l-(-)-.DELTA.9-Tetrahydrocannabinol [l(-)-.DELTA.9-THC] antagonized the effect of naloxone on ileum without affecting responses to acetylcholine. l-(-)-.DELTA.9-THC produced a stereospecific, dose-dependent (1-10 mg/kg orally) 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. l-(-)-.DELTA.9-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 3-10 mg/kg. Cannabinoids may be useful in opiate detoxification. The inhibition by l-(-)-.DELTA.9-THC of the action of naloxone in dependent ileum seems to be via reduction in acetylcholine release. Whereas the end result of l-(-)-.DELTA.9-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.

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