Concurrent administration of morphine to both supraspinal and spinal sites produced a multiplicative (synergistic) interaction for antinociception. The purpose of this study was to determine if supraspinal glutaminergic receptors are involved in the multiplicative interaction for antinociception induced by morphine. The antinociception was assessed by the tail-flick test. Effect of MK-801 [(+/-)-5-methyl-10, 11-dihydro-5H-dibenzo (a,d)cyclohepten-5,10-imine maleate], a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, or CNQX (6-Cyano-7-nitroquinoxaline-2,3-dione), a competitive non-NMDA receptor antagonist on inhibition of the tail-flick response induced by a combined i.t. and i.c.v. administration of morphine was studied. Either i.t. or i.c.v. administration of morphine alone at the dose of 0.2 microgram slightly increased inhibition of the tail-flick response. However, concurrent i.t. and i.c.v. injections of morphine at the dose of 0.2 microgram increased the inhibition of the tail-flick response in a synergistic manner. Various doses of MK-801 (0.01-1 microgram) or CNQX (0.05-0.5 microgram) pretreated i.c.v. alone did not show any antinociceptive effect. MK-801 pretreated i.c.v. for 10 min dose-dependently attenuated the inhibition of the tail-flick response induced by concurrent i.t. and i.c.v. injections of morphine. However, CNQX pretreated i.c.v. for 10 min did not affect the inhibition of the tail-flick response induced by concurrent i.t. and i.c.v. injections of morphine. Our results suggest that supraspinal NMDA but not non-NMDA receptors are involved in mediating the antinociception produced by morphine-induced multiplicative interaction between spinal and supraspinal sites.