Systemic or intracerebroventricular injection of NMDA receptor antagonists attenuates the antinociceptive activity of intrathecally administered NMDA receptor antagonists.

We have previously reported that the response latency in the mouse hot-plate test is affected differently by spinal intrathecal (i.t.) injection of competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, in that only the former produces an antinociceptive effect. Since the lipophilic non-competitive antagonists will redistribute rapidly from the spinal injection site, it is conceivable that they reach sites where they counteract the spinal antinociceptive effect. In the present study, we have tested this hypothesis by comparing the antinociceptive effect of the competitive NMDA receptor antagonist CGS 19755 and the non-competitive NMDA receptor antagonist MK-801 after i.t., intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration as well as after combinations thereof. CGS 19755 injected i.p. or i.c.v. and MK-801 injected i.p. or i.t. attenuated the antinociceptive effect of i.t. injected CGS 19755. Both i.p. and i.c.v. administration of either CGS 19755 or MK-801 dose-dependently impaired motor function without producing antinociceptive effects. Thus, the effect of CGS 19755 and MK-801 on the motor system was found to be separate from their antinociceptive effect. In a separate experiment, changes in hind-paw skin temperature were excluded as a possible confounding factor. These findings demonstrate that supraspinal systems can limit the spinal antinociceptive effect of NMDA receptor antagonists.