The role of NMDA receptors in opioid tolerance

The results of recent studies demonstrate that activation of the N-methyl- scD-aspartate (NMDA) receptor is involved in opioid tolerance. The specific aim of the present dissertation is to examine whether or not blockade of the NMDA receptor, and in particular antagonism at the glycine co-agonist site, is a viable approach to attenuate tolerance. The effect of MK-801, an NMDA receptor channel blocker, and ACEA-1328, a novel NMDA receptor/glycine site antagonist, was studied on opioid-induced antinociception and tolerance in mice.; In acute studies, mice were injected with MK-801 or ACEA-1328 followed by morphine, a {dollar}mu{dollar} opioid receptor agonist, and tested for antinociception. MK-801 blocked, whereas ACEA-1328 showed potentiation of the antinociceptive effect of morphine. ACEA-1328 also potentiated the antinociceptive effect of U50,488H, a {dollar}kappa{dollar} opioid receptor agonist. The two NMDA receptor antagonists were also examined for phencyclidine (PCP)-like motor stimulatory side effects. MK-801, but not ACEA-1328, produced a bell-shaped increase in motor activity in mice.; In chronic studies, mice were injected with MK-801 or ACEA-1328 either alone or in conjunction with an opioid receptor agonist. Chronic treatment with the NMDA receptor antagonists blocked morphine tolerance in the tail flick and formalin tests. Concurrent administration of ACEA-1328 with morphine also showed reversal of a pre-established tolerance in the tail flick test. Chronic treatment with the NMDA receptor antagonists, either alone or in combination with the opioid analgesics, did not alter the basal nociceptive responses in both animal models of pain. Nevertheless, chronic treatment with ACEA-1328 decreased the antinociceptive potency of U50,488H in the tail flick test. A trend toward blockade of {dollar}kappa{dollar}-opioid tolerance was also observed, however, the decrease in the potency of U50,488H induced by chronic administration of ACEA-1328 confounded the interpretation of the results. Taken together, the results clearly show that antagonism at the NMDA receptor channel or at the glycine co-agonist site attenuated morphine tolerance. However, the PCP-like motor stimulatory side effects were only observed with the NMDA receptor channel blocker MK-801.