Effects of N-methyl-D-aspartate receptor antagonists on the analgesia and tolerance to D-Ala2, Glu4 deltorphin II, a delta 2-opioid receptor agonist in mice.

The effects of MK-801, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor and of LY 235959, a competitive antagonist of the NMDA receptor on the analgesic action and development of tolerance to the analgesic action of D-Ala2, Glu4 deltorphin II (deltorphin II), a delta 2-opioid receptor agonist were determined in mice. Tolerance to deltorphin II was induced in male Swiss-Webster mice by twice daily intracerebroventricular (i.c.v.) injections of the drug (20 micrograms/mouse) for 4 days. To determine the effects of NMDA receptor antagonists, the drugs were injected intraperitoneally in appropriate doses 10 min before each injection of deltorphin II. The doses of MK-801 were 0.01, 0.03 or 0.10 mg/kg whereas those of LY 235959 were 1, 2 or 4 mg/kg. Chronic administration of NMDA receptor antagonists by themselves did not alter the tail-flick latency or the analgesic effect of deltorphin II. MK-801 given concurrently with deltorphin II inhibited the development of tolerance to deltorphin II, the significant effects were observed at 0.03 and 0.10 mg/kg doses. Similar inhibitory effect of development of tolerance to deltorphin II were observed with LY 235959 at 4 mg/kg dose. MK-801 and LY 235959 also antagonized the analgesic action of deltorphin II. It is concluded that antagonism of NMDA receptors attenuates the analgesic action as well as development of tolerance to the analgesic action of delta 2-opioid receptor agonist in the mouse.