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

Purpose: To investigate the interaction of midazolam and N-methyl-D-asparta te (NMDA) receptor or -amino3- hydroxy-5-methyl isoxazole-4-propionic acid (AMPA) receptor antagonist on the effects of persistent inflammatory nocice ptive activation. Methods: Male Sprague-Dawley rats were implanted with lumbar intrathecal ca theters and were tested for their responses to subcutaneous formalin inject ion into the hindpaw. Saline, midazolam (1 to 100 ug), AP-5 (1 to 30 mug), a NMDA receptor antagonist, or YM872 (0.3 to 30 mug), an AMPA receptor anta gonist was injected intrathecally 10 min before formalin injection. The com binations 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 is obologram. Results: Dose-dependent effects were observed with midazolam (ED50 was 1.34 mug and 1.2 1 mug in phase 1 and 2 of the formalin test, respectively), AP -5 (7.64 mug and 1.4 mug) and YM872 (0.24 mug and 0.2 1 mug). Synergistic e ffects in both phases were obtained when combining midazolam with AP-5 or Y M872. The ED50 of midazolam decreased to 0.012 mug (phase 1) and 0.27 mug ( phase 2) with AP-5 and to 0.09 mug (phase 2) and 0.35 mug (phase 2) with YM 872 (P < 0.01). Conclusions: 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.