N-Methyl-D-Aspartate Receptors in Opioid Dependence and Withdrawal

Abstract

The etiology of neurochemical, electrophysiological and behavioral expressions that accompany, indeed define, withdrawal from dependence on opioids remains elusive. However, recent evidence has emphasized three key features of opioid withdrawal. First, increased firing rates (hyperactivity) of noradrenergic neurons in the locus ceruleus correlate strongly with behavioral signs and symptoms of withdrawal (Rasmussen et al., 1990). Second, the majority of this hyperactivity (as much as 80%) is elicited as a result of increases in afferent excitatory glutamatergic input to these neurons (Akaoka and Aston-Jones, 1991; Aston-Jones et al., 1997). Third and finally, the predominant (but not necessarily the sole) source for this excitatory input is the nucleus paragigantocellularis (PGi) in the ventrolateral medulla (Akaoka and Aston-Jones, 1991). The receptor or receptors that mediate the glutamatergic excitatory input have yet to be resolved, although the N-methyl-D-aspartate (NMDA) ionotropic glutamate subtype has been implicated. The results presented here summarize our evidence for an involvement of NMDA receptors in opioid dependence and withdrawal phenomena (Zhu and Ho, 1998; Zhu et al., 1999).