Afferent effects on locus coeruleus in opiate withdrawal.

The locus coeruleus (LC) has been hypothesized to play an important role in opiate withdrawal. This hypothesis is supported, in part, by the finding that LC neurons greatly increase their activity during antagonist-precipitated morphine withdrawal and that this increased activity correlates temporally with withdrawal behavior. However, this withdrawal-induced increase in unit activity is not seen in vitro in brain slices taken from morphine-dependent animals, indicating that afferents to the LC play an important role in the withdrawal-induced activation of these neurons. This chapter reviews data indicating: (1) the morphine-withdrawal-induced activation of LC neurons is mediated predominantly by non-N-methyl-D-aspartate (NMDA) excitatory amino acid pathways in the brain; (2) the activation of the LC during morphine withdrawal may be mediated, at least in part, by an excitatory amino acid projection from the nucleus paragigantocellularis. The role of other excitatory amino acid pathways in the withdrawal-induced activation of the LC remains to be determined; (3) intrinsic changes in the G-protein/cyclic AMP system of LC cells may play an important role in mediating the effects of afferent inputs to the LC during morphine withdrawal; (4) NMDA antagonists (unlike the alpha 2 agonist clonidine) attenuate the behavioral signs of morphine withdrawal without blocking the withdrawal-induced increase of LC unit activity. In addition, non-competitive NMDA antagonists like MK801 may not be useful to alleviate opiate-withdrawal symptoms in man because of their PCP-like side effects. However, competitive NMDA antagonists like LY274614 could be of great benefit for alleviating opiate-withdrawal withdrawal symptoms in man.