The role of the locus coeruleus and N-methyl-D-aspartic acid (NMDA) and AMPA receptors in opiate withdrawal.

Biochemical, behavioral, and electrophysiologic studies indicate that activation of the noradrenergic cells in the locus coeruleus (LC) plays an important role in the symptoms of opiate withdrawal. Extrinsic factors play a major role in the morphine-withdrawal-induced activation of the LC, but intrinsic factors also play a role. Among the extrinsic factors, a glutamatergic projection from the nucleus paragigantocellularis plays an important role in the withdrawal-induced activation of the LC. N-methyl-D-aspartic acid (NMDA) receptors play at most a minor role in the withdrawal-induced activation of the LC by glutamate; preliminary evidence indicates that alpha-amino-3 hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors play an important role. Whereas NMDA antagonists produce little to no suppression of the activation of the LC during morphine withdrawal, they do suppress many morphine withdrawal symptoms. However, phencyclidinelike side effects may limit the clinical utility of NMDA antagonists. Experiments examining c-fos expression during morphine withdrawal indicate that NMDA antagonists may exert some of their influence on morphine withdrawal symptoms through actions in the forebrain. Pretreatment with the noncompetitive NMDA antagonist MK801 blocks morphine withdrawal-induced increased c-fos expression in the amygdala, but not in the nucleus accumbens, frontal cortex, or hippocampus. Pretreatment with the competitive NMDA antagonist LY274614 (or the alpha2-adrenergic agonist clonidine) blocks morphine withdrawal-induced increased c-fos expression in the amygdala and nucleus accumbens, but not in the frontal cortex or hippocampus. These results help to elucidate some of the neuroanatomy and neurophysiology underlying morphine withdrawal. Further, NMDA antagonists may not be clinically useful for opiate withdrawal due to their side-effects, but AMPA antagonists may be of great benefit for alleviating opiate withdrawal symptoms in humans.