Role of spinal and supraspinal muscarinic receptors in the expression of morphine withdrawal symptoms in the rat.

Previous studies in this laboratory have demonstrated that prior intracerebroventricular (i.c.v.) administration of the muscarinic antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) in morphine dependent rats significantly attenuates the development of cardiovascular and certain behavioral responses precipitated by the opiate antagonist, naloxone. The purpose of this study was to determine whether both supraspinal and spinal cholinergic neurons are involved in the expression of withdrawal symptoms. Employing localized (i.c.v. or intrathecal, i.t.) infusions of muscarinic antagonists, it was determined that a significant antiwithdrawal action could be produced through both an inhibition of supraspinal and spinal cholinergic neurons. Pharmacological difference emerged regarding the antiwithdrawal potential of 4-DAMP and the partially M1 selective antagonist, pirenzepine. While our previous studies had revealed that pirenzepine had essentially no antiwithdrawal activity when administered by the i.c.v. route, in the present study, pirenzepine evoked a marked antiwithdrawal action by the i.t. route, significantly inhibiting both cardiovascular and behavioral signs of withdrawal. In contrast, 4-DAMP which was effective by the i.c.v. route (especially for the cardiovascular symptoms), elicited no antiwithdrawal action by the i.t. route. As a muscarinic antagonist (ability to block the pressor response to central injection of carbachol) 4-DAMP was equally active by i.c.v. or i.t. injection. However, pirenzepine was clearly more effective in this regard by the i.t. route. These results are consistent with ability of muscarinic antagonists to offer significant anti-morphine withdrawal activity at both supraspinal and spinal locations. They also suggest that different muscarinic systems, possibly different receptor subtypes, mediate the expression of morphine withdrawal symptoms within the two regions of the CNS.