Cardiovascular and behavioral changes associated with morphine abstinence in the physically dependent rat: a neuropharmacological study of both the spinal and supraspinal components of withdrawal

Abstract

·.Physical depende.nce upon narcotics is, revealed in a characterfstic withdrawal syndrome of autonomic and behavioral changes evoked· by the administration of a narcotic antagonist. Although these changes have bee~ described, the mechanisms and locations within the central nervous system responsible for these effects are· unknown. My research was designed to develop an .objective animal model of dependency which could be used to identify mechanisms associated with narco.tic wi t.hdrawal. Cardiovascular and behavioral responses were ~valuat·ed following naloxone administration to·. freely moving rats made. physically dependent by a chronic intra-ar~ terial infusion of.morphine over 5 days. Naloxone evoked an elevation in mean arterial pressure (M·:AP) which· increased in a dose. and time dependent manner over the infusion schedule·whereas traditional behavioral signs of withdrawal were variable. Cardiovascular and behavioral signs of withdra~al also were e.lici ted by regional naloxone injection into various areas of the central nervo.us system including the spinal cord. Intrathecally administered, anticholinergic agents reduced the naloxone-induced increase in MAP along with some behavioral si.gns of wi thdr·awal. Spinal-t.ransected ( V.l), I dependent rats generated a profound hypertensive response to naloxone which was abolished·. by ganglionic or ct-adrenergic. blockade, spinal pithing or surgical dorsal root section. .Anticholinergic agents, intrathecally administered to spin~l-transected rats, resulted in an augmented hypertensive r~sponse to naloxone. These results indicate that 1) the naloxone-induced increase (MAP) in morphine dependent rats can serve as an objective and more sensitive measure of the degree of physical dependence than behavioral responses of withdrawal, 2) the spinal cord is capable of initiating cardiovascular and behavioral signs of withdrawal which can be modified by intrathecal administration of anticholinergic agents, 3) independent of supraspinal influences the spinal cord itself can generate a profound_ increase in mean arterial pressure which requires afferent information for its expression and, 4) at least two opposing cholinergic mechanisms which regulate cardiovascular activity exist with~n the spinal cord; one which is descending and facilitatory and another which is intrinsic and inhibitory.