Our previous studies have demonstrated that supraspinal glutamate receptors are differentially involved in the antinociception induced by morphine and beta-endorphin given intracerebroventricularly (i.c.v.) in the tail-flick and hot-plate tests. The formalin pain test was used in the present study. Injection of mice with formalin solution (2%, 10 microl) into the hindpaw intraplantarly produced the first (0-5 min) and second (20-40 min) phases of formalin responses. The formalin responses in the both phases were attenuated dose-dependently by morphine (0.125-1 microg) or beta-endorphin (0.125-1 microg) administered i.c.v. 5 min before. The antinociceptive effect of morphine was slightly more potent in the second phase whereas the effect of beta-endorphin was more pronounced in the first phase. MK-801 (0.1-1 microg), a non-competitive NMDA receptor antagonist, and CNQX (0.05-0.5 microg), a non-NMDA antagonist, given i.c.v., produced antinociceptive effect in the both phases, but only in a partial manner. Both MK-801 (0.05 microg) and CNQX (0.01 microg), at the dose which had no intrinsic effect, reversed the antinociceptive effect of beta-endorphin (1 microg) observed during the second, but not the first, phase partially but significantly. However, the antinociceptive effect of morphine (1 microg) was not affected by the same dose of MK-801 or CNQX given i.c.v. Our results indicate that, at the supraspinal level, both NMDA and non-NMDA receptors are involved in the production of antinociception induced by supraspinally administered beta-endorphin, but not morphine, in the formalin pain model.