Kurt Rasmussen, PhD
Cessation of the repeated administration of opiates results in a characteristic morbidity in humans, including anxiety, nausea, insomnia, hot and cold flashes, muscle aches, perspiration, and diarrhea (1). Great strides have been made in understanding the neurophysiology underlying these opiate-withdrawal symptoms. Several neurotransmitter systems have been shown to play an important role in opiate withdrawal, including the dopaminergic (2-4) and cholinergic (5-7) systems. This chapter will discuss evidence for a role of the glutamate system in morphine withdrawal. Specifically, the idea that morphine withdrawal is a state of glutamate hyperactivity in defined brain regions will be discussed. One of those brain regions is the locus coeruleus.
The locus coeruleus (LC) is the largest cluster of noradrenergic neurons in the mammalian brain (8,9). Although the cell bodies are confined to a small area near the forth ventricle in the anterior pons, LC neurons send projections to most of the central nervous system, including the cerebral cortex, hippocampus, cerebellum, and spinal cord (10,11). Owing to these wide-ranging projections, the LC is in a position to influence the activity of many parts of the neuraxis and has been hypothesized to play a role in many behaviors, physiological processes, and disease states.
The LC receives numerous afferent inputs. Sites sending projections to the LC include the nucleus paragigantocellularis (PGi), the prepositus hypoglossi, subregions of the hypothalamus, the Kol-liker-Fuse nucleus, the periaquaductal gray, Barrington's nucleus in the brainstem, the nucleus of the solitary tract, and the central nucleus of the amygdala (12-16). The projection to the LC from the PGi has both inhibitory and excitatory components and has a strong influence on the activity of LC neurons. The excitatory input from the PGi is mediated, at least in part, via glutamatergic projections (17) and has been shown to play an important role in the activation of the LC observed during morphine withdrawal (18).
In opiate-dependent rats, the activity of LC neurons increases dramatically during antagonist-precipitated withdrawal (19-22). This increased activity of the LC has been hypothesized to play an important role in opiate-withdrawal symptoms. This hypothesis is supported by several lines of evidence. First, the increased activity of LC neurons correlates temporally with withdrawal behaviors
From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ
(21). Second, administration of clonidine, an a2-adrenergic receptor agonist (either systemically or locally infused into the LC), suppresses the increased LC unit activity (19), the increase in norepinephrine turnover and release in LC projection areas (23-25), and many behavioral symptoms (26-28) seen during opiate withdrawal. Third, destruction of the LC decreases physical signs of opiate withdrawal (29). Fourth, the LC is the most sensitive site for the induction of withdrawal signs following the local injection of an opiate antagonist (30).
However, the role of the LC in opiate withdrawal has also been questioned. In one study, a neuro-chemical lesion of the LC did not alter opiate-withdrawal symptoms or the ability of clonidine to reverse opiate withdrawal (31). In addition, lesions of LC noradrenergic projections did not alter opiate-withdrawal-induced conditioned place aversion (32). Indeed, some investigators have suggested that brain structures which are independent of the LC-noradrenergic system play a more important role in the expression of opiate-withdrawal symptoms (33). Whatever the precise role of the LC in the production of opiate-withdrawal symptoms, there is clearly a strong activation of LC neurons during opiate withdrawal. This strong activation of LC neurons can serve as a model of glutamate hyperactivity during opiate withdrawal.
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