Effects of cholinergic and anticholinergic drugs and a partial cholinergic agonist on the development and expression of physical dependence on morphine in rat.

Cholinergic and anticholinergic agents were tested against the induction and expression of morphine dependence in rats. Mecamylamine hydrochloride, administered during abstinence, exacerbated the syndrome at the time of peak severity (20-40 hours after with-holding morphine) but accelerated the subsequent decline in severity of withdrawal. Atropine sulfate acted similarly but none of its effects proved statistically significant. When administered together, these drugs were not additive but were antagonistic in their central actions at the time of peak withdrawal. Atropine methylnitrate reduced withdrawal severity throughout the observation period mainly by antagonism of the peripheral expression of many of the parasympathetic signs. Eserine sulfate administered during the period of habituation or of abstinence had little effect on the severity of the total withdrawal syndrome but decreased weight loss. Choline chloride effectively reduced overall withdrawal severity and weight loss throughout the entire course of withdrawal monitored for up to 100 hours after withholding morphine. This occurred whether choline was administered during morphine habituation or after withholding the morphine. These results support the view that a derangement of cholinergic function is a factor in the morphine abstinence syndrome; evidence is yet lacking to decide whether this is the primary derangement of neurotransmitter function. The effectiveness of choline may be explained by its action as a partial agonist to normalize cholinergic function at all stages of derangement. The reduction in withdrawal severity by treatment with choline during the habituation to morphine indicates an inhibition of the development of dependence rather than mere suppression of the signs during withdrawal.