The effects of MK-801, a noncompetitive antagonist of the N-methy1-D-aspartate (NMDA) receptor, and of LY 235959, a competitive antagonist of the NMDA receptor, on the development of tolerance to the analgesic action of [D-Pen2,D-Pen5]enkephalin (DPDPE), a delta 1-opioid receptor agonist were determined in mice. Tolerance to DPDPE was induced in male Swiss Webster mice by twice daily ICV injections of the drug (20 micrograms/mouse) for 4 days. To determine the effects of NMDA receptor antagonists, the drugs were injected IP in appropriate doses 10 min before each injection of DPDPE. The doses of MK-801 were 0.01, 0.03, and 0.10 mg/kg whereas those of LY 235959 were 1, 2, and 4 mg/kg. Chronic administration of NMDA receptor antagonists by themselves did not alter the tail flick response or the analgesic effect of DPDPE (10 micrograms/mouse, ICV). MK-801 given concurrently with DPDPE dose-dependently inhibited the development of tolerance to DPDPE, the significant effect being observed at 0.10 mg/kg dose. Similar inhibitory effects on the development of tolerance to DPDPE were observed with LY 235959 at 1, 2, and 4 mg/kg doses. It is concluded that antagonism of NMDA receptors blocks tolerance to the analgesic action of delta 1-opioid receptor agonist in the mouse.