Spinal cholinergic neurons and the expression of morphine withdrawal symptoms in the rat

Abstract

Behavioral and autonomic signs of the morphine withdrawal syndrome were measured in dependent rats injected with the opiate antagonist naloxone. The purpose of this study was to determine whether spinal cholinergic pathways play a role in the expression of spinally mediated withdrawal symptoms. lntrathecal (i.t.) administration of 1 pg carbachol or 5 ccg neostigmine resulted in increases in mean anterial pressure (MAP) of 32 and 45 mm Hg, respectively, in conscious, freely moving rats. The pressor response to carbachol began almost immediately after injection, but that to neostigmine was delayed in onset. Both responses were completely abolished following i.v. injection of 2 mg/kg atropine. However, in spinal-transected (C-l ), ventilated rats, i.t. injection of carbachol or neostigmine resulted in only small, transient increases in MAP. Intraarterial (i.a.) injection of 0.5 mg/kg naloxone to morphine-dependent rats resulted in an immediate increase in MAP (to 33 mm Hg) that lasted at least 1 hr. This was accompanied by classical behavioral signs of withdrawal. Pretreatment of dependent rats with i.t. injection of atropine or hemicholinium3 (HC-3) significantly reduced the pressor and several behavioral responses elicited by naloxone. In contrast, when morphine-dependent, spinal-transected rats were pretreated with i.t. injection of cholinergic antagonists, i.a. injection of naloxone resulted in an enhanced MAP response. Finally, in intact dependent rats, i.t. injection of naloxone (6 pg) produced a 14 mm Hg increase in MAP that was significantly augmented (21 mm Hg) following i.t. pretreatment with HC-3. These results may be explained by the presence of a descending spinal cholinergic pathway that facilitates the autonomic component of morphine withdrawal and an intrinsic spinal cholinergic pathway that is inhibitory to the expression of withdrawal.In drug-dependent rats, there is a significant pressor response associated with morphine withdrawal following systemic injection of the narcotic antagonist naloxone. Behavioral and autonomic signs of withdrawal can be elicited following the intraarterial (i.a.) injection (Buccafusco, 1983) of naloxone, as well as by injection of naloxone into localized areas of the CNS. For example, injection of naloxone into the lateral or fourth cerebral

Naloxone‐induced cardiovascular depression in rats that had received chronic morphine‐treatment

“…It was found in the present study that atropine pretreatment dose-dependently reduced the incidence of occurrence of faecal passage and muscle twitching following naloxone injection. This is in agreement with the findings of Chang et al (1984) and Marshall & Buccafusco (1987). However, the current investigation also revealed that atropine pretreatment did not markedly affect the circulatory depression or the occurrence of cardiac extrasystoles after naloxone administration.…”

“…This indicates that cholinergic hyperactivity is not involved in the cardiovascular responses of chronically morphine-treated rats to naloxone-precipitated opiate withdrawal. It may not be reasonable to compare this postulation with that of Marshall & Buccafusco (1987) who made their observations in conscious and freely moving morphine-dependent rats. Based on the preventive effects of intrathecal injection of atropine or hemicholinium-3, they suggested that the blood pressure increases induced by naloxone administration resulted from central cholinergic hyperactivity which evoked an augmentation of sympathetic activity.…”

“…The underlying mechanisms are not clearly understood. During narcotic withdrawal, there is central cholinergic hyperactivity, augmented sympathetic outflow, and enhanced effects of a number of neurotransmitters and neuromodulators in certain organs such as gut (Chang et al, 1984;Marshall & Buccafusco, 1987). These, as well as other endogenous changes, have been implicated in the production of some withdrawal symptoms.…”

Intentional Intrathecal Opioid Detoxification in 3 Patients: Characterization of the Intrathecal Opioid Withdrawal Syndrome

“…Although the mechanism is unclear, cholinergic stimulation at the level of the spinal cord typically augments sympathetic activity and results in hypertension. Anticholinergic administration to rats experiencing opioid withdrawal results in a blunting of autonomic pressor response; however, this requires an intact spinal cord, suggesting a descending spinal cholinergic pathway that facilitates the autonomic response to IT opioid withdrawal 66,67 . This cholinergic excitatory descending pathway activates sympathoexcitatory preganglionic synapses in the case of an intact spinal cord, and IT clonidine reduces post‐withdrawal increases in MAP via interaction with cholinergic neurons.…”

Neurobiology of nAChRs and cognition: A mini review of Dr. Jerry J. Buccafusco's contributions over a 25 year career

“…Around this same time Dr. Buccafusco also began working in the field of drug abuse research, the beginnings of his long time participation in the Veteran's Administration Merit system. These studies focused on the role of central cholinergic neurons in the development of physical dependence on opiates, the expression of withdrawal symptoms, and the return to drug-seeking behavior [4]. …”