The N-methyl-D-aspartate (NMDA) and metabotropic glutamate (mGlu) receptors are involved in nociceptive transmission in the central nervous system. The present study was designed to study the effects of NMDA and group I mGlu receptor agents on delta- and mu-opioid receptor agonist-induced antinociception in the mouse brain. Intracerebroventricular (i.c.v.) treatment with the non-competitive NMDA receptor antagonist dizocilpine and the group I mGlu receptor antagonist (S)-4-carboxyphenylglycine ((S)-4CPG) significantly attenuated the antinociception induced by the delta-opioid receptor agonists [D-Pen(2), Pen(5)]enkephalin (DPDPE), (-)-TAN 67 and [D-Ala(2)]deltorphin II. On the contrary, i.c.v. administration of dizocilpine and (S)-4CPG slightly but significantly enhanced the antinociception induced by the mu-opioid receptor agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]enkephalin (DAMGO). Under these conditions, i.c.v. administration of NMDA and the group I mGlu receptor agonist 3,5-dihydrophenylglycine (DHPG) significantly enhanced the antinociception induced by delta-opioid receptor agonists, whereas both reduced DAMGO-induced antinociception. These findings suggest that the supraspinal antinociceptive actions of mu- and delta-opioid receptor agonists appear to be modulated differently by NMDA and group I mGlu receptors in the mouse.