Synergistic analgesic effects of intrathecal midazolam and NMDA or AMPA receptor antagonists in rats.

Abstract

To investigate the interaction of midazolam and N-methyl-D-aspartate (NMDA) receptor or -amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA) receptor antagonist on the effects of persistent inflammatory nociceptive activation. Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters and were tested for their responses to subcutaneous formalin injection into the hindpaw. Saline, midazolam (1 to 100 microg), AP-5 (I to 30 microg), a NMDA receptor antagonist, or YM872 (0.3 to 30 microg), an AMPA receptor antagonist was injected intrathecally 10 min before formalin injection. The combinations of midazolam and AP-5 or YM872 in a constant dose ratio based on the 50% effective dose (ED50) were also tested and were analysed with an isobologram. Dose-dependent effects were observed with midazolam (ED50 was 1.34 microg and 1.21 microg in phase 1 and 2 of the formalin test, respectively), AP-5 (7.64 microg and 1.4 microg) and YM872 (0.24 microg and 0.21 microg). Synergistic effects in both phases were obtained when combining midazolam with AP-5 or YM872. The ED50 of midazolam decreased to 0.012 microg (phase 1) and 0.27 microg (phase 2) with AP-5 and to 0.09 microg (phase 1) and 0.35 microg (phase 2) with YM872 (P < 0.01). These results suggest a functional coupling of benzodiazepine-aminobutyric acid (GABA)A receptor with NMDA and AMPA receptors in acute and persistent inflammatory nociceptive mechanisms in the spinal cord.