The present study was designed to determine whether the increase in N-methyl-d-aspartate (NMDA) activity in the mouse spinal cord, unmasked by naloxone in morphine-pretreated mice, is mediated by sigma receptor activity. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.) except when NMDA was injected together with 0.1 μg of naloxone. This excitatory effect of morphine on NMDA-induced behaviors, unmasked in the presence of naloxone was prevented but not reversed by haloperidol, a sigma ligand and dopamine antagonist, but not by an equivalent dose of spiperone, a dopamine antagonist. Sigma activity also appeared to contribute to morphine withdrawal jumping in mice as haloperidol inhibited naloxone-induced jumping while spiperone did not. Together these data indicate that naloxone unmasks an action of morphine on NMDA and during acute withdrawal, and these effects are each brought about by mechanisms involving sigma receptor activity.