BackgroundTwo major neurotransmitters, [Greek small letter gamma]‐aminobutyric acid (GABA) and the excitatory amino acid, glutamate, may be involved in nociception in the spinal cord. GABA and glutamate receptors may operate in concert to modify signals in the central nervous system. The purpose of this study was to investigate the spinal analgesic interaction between midazolam, a benzodiazepine‐GABAAreceptor agonist, and two glutamate receptor antagonists on acute thermal nociception.MethodsSprague‐Dawley rats were implanted with chronic lumbar intrathecal catheters and were tested for their tail withdrawal response by the tail flick test after intrathecal administration of saline, midazolam (1–100 [micro sign]g), AP‐5 (1–30 [micro sign]g), or YM872 (0.3–30 [micro sign]g). AP‐5 is an N‐methyl‐D‐aspartate (NMDA) receptor antagonist and YM872 is an [Greek small letter alpha]‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptor antagonist. The combination of midazolam and the other two agents were also tested by isobolographic analyses. Motor disturbance and behavioral changes were observed.ResultsDose‐dependent increases in the tail flick latency were observed with midazolam, AP‐5, and YM872 with 50% effective dose values of 1.57 +/‐ 0.34 (SEM) [micro sign]g, 5.54 +/‐ 0.19 [micro sign]g, and 1.0 +/‐ 0.22 [micro sign]g, respectively. A potent synergy in analgesia with decreased behavioral changes and motor disturbance was obtained when combining midazolam with AP‐5 or YM872.ConclusionsSpinally administered midazolam and an NMDA‐ or an AMPA‐receptor antagonist exhibited potent synergistic analgesia on acute thermal nociception in rats. Side effects, shown by behavioral changes and motor disturbance, decreased with the combination of the agents. These results point out an important direction for the study of acute nociception.