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

Tomoki Nishiyama, MD PhD^*,, Laszlo Gyermek, MD PhD, Chingmuh Lee, MD, Sachiko Kawasaki-Yatsugi, PhD and Tokio Yamaguchi, PhD

^* From the Department of Surgical Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan, the Department of Anesthesiology,
Harbor-University of California, Los Angeles Medical Center, Torrance, California, USA, and the Institute for Drug Discovery Research,
Yamanouchi Pharmaceutical Company, Ibaraki, Japan.

Address correspondence to: Dr. Tomoki Nishiyama, 3-2-6-603, Kawaguchi, Kawaguchi-shi, Saitama, 332-0015, Japan. Phone: 81-3-5449-5356 (Dept.); Fax. 81-3-5449-5356 (Dept.); E-mail: nishiyam{at}ims.u-tokyo.ac.jp

Purpose: 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.

Methods: 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 µg), AP-5 (1 to 30 µg), a NMDA receptor antagonist, or YM872 (0.3 to 30 µg), 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.

Results: Dose-dependent effects were observed with midazolam (ED₅₀ was 1.34 µg and 1.21 µg in phase 1 and 2 of the formalin test, respectively), AP-5 (7.64 µg and 1.4 µg) and YM872 (0.24 µg and 0.21 µg). Synergistic effects in both phases were obtained when combining midazolam with AP-5 or YM872. The ED₅₀ of midazolam decreased to 0.012 µg (phase 1) and 0.27 µg (phase 2) with AP-5 and to 0.09 µg (phase 1) and 0.35 µg (phase 2) with YM872 (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.

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