SITES OF ACUTE MORPHINE TOLERANCE IN INTESTINE

¹ Department of Pharmacology, The University of Texas Medical School at Houston, Texas Medical Center, Houston, Texas

Experiments were performed to differentiate between neurotransmitter receptors and narcotic receptors as sites for acute narcotic tolerance in dog intestine. Intestinal motor responses to bolus intra-arterial injections of morphine, 5-hydroxytryptamine (5-HT), bethanechol and dimethylphenylpiperazinium were measured in isolated small bowel segments. The vasculature of the isolated segments was perfused with Krebs-bicarbonate solution (control) or with Krebs' solution containing morphine, levorphanol, naloxone or 5-HT. During perfusion of gut segments with morphine (2 µg/ml), intestinal motor responses to bolus doses of morphine were significantly reduced (acute tolerance). Responses to 5-HT, bethanechol and dimethylphenylpiperazinium were not reduced. Perfusion of segments with levorphanol (0.2 µg/ml) reduced responses to 5-HT slightly and reduced responses to morphine considerably. Levorphanol did not alter responses to bethanechol and dimethylphenylpiperazinium. Naloxone (2 µg/ml) perfusion, like morphine perfusion, reduced responses to morphine selectively. Responses to both morphine and 5-HT were reduced during perfusion of bowel segments with 5-HT (20 µg/ml). Previous studies have indicated that both 5-HT and cholinergic receptors are involved in the intestinal stimulatory response to morphine (Burks, T. F. J. Pharmacol. Exp. Ther. 185: 530-539, 1973). Acute tolerance or tachyphylaxis to the narcotics, however, did not prevent responses to 5-HT and the cholinergic agonists. These observations thus suggest that acute tolerance to morphine results from events expressed at the level of the narcotic receptor. Reduced responsiveness to morphine occurs during tachyphylaxis to 5-HT apparently because morphine's stimulatory effects are mediated in part by 5-HT.

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