EFFECTS OF NARCOTIC ANALGESIC AGONISTS AND ANTAGONISTS ON RAT BRAIN ACETYLCHOLINE

¹ Michigan Neuropsychopharmacology Research Program, Department of Pharmacology, University of Michigan, Ann Arbor, Michigan

Various narcotics were given i.p. to groups of 8 to 12 young (20-30 days) and adult (90 + days) male albino rats in order to measure their effects on steady-state total brain acetylcholine (ACh) as well as after its depletion mainly by intraventricular (ivt.) hemicholinium-3 (HC-3) or acetylseco HC-3. Relatively small doses of morphine (10 mg/kg) and related agonists showed no significant changes in steady-state levels of brain ACh. However, rather remarkable ACh-antidepleting effects were observed. The dose-effect relations in nontolerant and tolerant animals were determined. In addition, the effects of the narcotic antagonists nalorphine and naloxone, thebaine, and the isomers of methadone were examined in an attempt to determine whether ACh antidepletion was a specific effect of narcotic agonists. Sedatives such as pentobarbital in anesthetic doses also prevented HC-3 depletion of brain ACh, but were not antagonized by nalorphine. LSD-25 and methotrimeprazine, which have been reported to produce analgesia in man, did not prevent brain ACh depletion by HC-3. After morphine injection twice daily for two weeks to a maximal dose of 200 mg/kg, groups of rats were abruptly withdrawn or given nalorphine. Steady-state as well as brain ACh levels after 20 µg of HC-3 ivt. and 5 and 20 µg of acetylseco HC-3 ivt. were determined. The data obtained are consistent with the hypothesis that one of the specific actions of narcotic agonists is to prevent depletion of brain ACh in the rat not only by HC-3 but also by scopolamine and acetylseco HC-3. During morphine withdrawal, brain ACh depletion induced by 5 µg of acetylseco HC-3 ivt. seems to be enhanced.

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