Prevention of morphine-induced muscarinic (M2) receptor adaptation suppresses the expression of withdrawal symptoms.

Treatment of opiate addiction is generally directed at the suppression of withdrawal symptoms through maintenance of the 'addicted' state with methadone. Yet relatively little is known regarding the neural substrates that contribute to, and maintain the prolonged state of withdrawal experienced by addicts. Opiates can profoundly alter the dynamics of brain and peripheral cholinergic systems, and central administration of anticholinergic drugs in dependent rats has been shown to decrease the expression of precipitated withdrawal symptoms. The purpose of this study was to determine whether the adaptive changes to M2 muscarinic receptors in autonomic centers are linked to the expression of withdrawal phenomena. During the peak period of withdrawal, there was a significant increase in both the expression of M2 muscarinic receptors and its corresponding mRNA within the rostral ventrolateral medulla, a primary vasomotor region. That most of these changes in receptor expression were adaptive in nature was suggested by the fact that when the acetylcholinesterase inhibitor DFP was co-administered with morphine, both the increased mRNA expression and the appearance of withdrawal symptoms were inhibited. Thus, interference with morphine-induced M2 muscarinic receptor adaptation in critical brain regions was correlated with a reduction in the development of physical dependence.