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Interaction between midazolam and epibatidine in spinally mediated antinociception in rats

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Abstract

Purpose

Both γ-aminobutyric acid (GABA)A receptors and nicotinic cholinergic receptors have important roles in antinociception in the spinal cord. The antinociceptive effects of midazolam (a GABAA 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.

Methods

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.

Results

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.

Conclusion

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.

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Authors and Affiliations

  1. Department of Anesthesiology and Critical Care, Kamagaya General Hospital, 926-6 Hatsutomi, Kamagaya, 273-0121, Japan

    Tomoki Nishiyama

  2. 3-2-6-603 Kawaguchi, Kawaguchi, 332-0015, Japan

    Tomoki Nishiyama

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  1. Tomoki Nishiyama
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Additional information

This work was done at the Department of Anesthesiology, The University of Tokyo.

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Nishiyama, T. Interaction between midazolam and epibatidine in spinally mediated antinociception in rats. J Anesth 23, 370–377 (2009). https://doi.org/10.1007/s00540-009-0765-0

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  • DOI: https://doi.org/10.1007/s00540-009-0765-0

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