Interaction between midazolam and epibatidine in spinally mediated antinociception in rats

Abstract

Both gamma-aminobutyric acid (GABA)(A) receptors and nicotinic cholinergic receptors have important roles in antinociception in the spinal cord. The antinociceptive effects of midazolam (a GABA(A) agonist) and epibatidine (a nicotinic cholinergic agonist) in the spinal cord have been reported. The present study was performed to investigate the interaction between intrathecal midazolam and epibatidine. Sprague-Dawley rats with lumbar intrathecal catheters were tested for their tail withdrawal response to thermal stimulation (tail-flick test) or for their paw flinches in response to formalin injection (formalin test) after the intrathecal administration of epibatidine or a combination of midazolam and epibatidine. The combination doses were 1/16, 1/8, 1/4, 1/2, 1, 2, and 4 times the 50% effective dose (ED50) of each agent in each test. The interaction of midazolam and epibatidine was investigated by isobolographic analysis. Behavioral side effects were also investigated. In the tail-flick test, the ED50 values of the combination were significantly higher than the theoretical additive values. In the formalin test, the ED50 values of the combination were significantly lower than the theoretical additive values in phase 1, but were not different from the theoretical additive values in phase 2. The intrathecal combination of midazolam and epibatidine had antagonistic effects on thermal acute nociception, while the combination had synergistic effects on acute inflammatory nociception, with only additive effects on inflammatory-facilitated nociceptive responses.