Interaction between a NMDA receptor antagonist, AP-5 and an AMPA receptor antagonist, YM 872 in antinociception in the spinal cord.

Abstract

The intrathecal N-methyl-D-aspartate (NMDA) receptor antagonist, AP-5 and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, YM 872 showed inhibition on both acute and facilitated nociception in our previous study. The present study was performed to investigate the interaction between intrathecal AP-5 and YM 872 in antinociception for acute and chronic nociception. Sprague-Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and for their paw flinches by formalin injection after intrathecal administration of AP-5 or YM 872. The effects of the combination were tested by an isobolographic analysis using 50% effective dose (ED50). Total fractional dose was calculated as (ED50 dose of AP-5 in combination)/(ED50 dose of AP-5 alone)+(ED50 dose of YM 872 in combination)/(ED50 dose of YM 872 alone). Intrathecally administered AP-5, YM 872, and their combination produced dose-dependent increases of the tail-flick latency and decreases in the number of flinches in both phase 1 and 2 of the formalin test. The ED50 values of the combination were significantly lower than the calculated additive values (P<0.01). Total fractional dose value was 0.22 in the tail flick test, 0.12 in the phase 1 and 0.14 in the phase 2 of the formalin test. An NMDA receptor antagonist, AP-5 and an AMPA receptor antagonist, YM 872 had synergistic antinociceptive effects on both acute thermal and inflammatory induced acute and facilitated nociception.