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Interaction between midazolam and epibatidine in spinally mediated antinociception in rats

Journal of Anesthesia volume 23, pages 370–377 (2009)Cite this article

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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References

  1. Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology. 1990;73:273–277.

    PubMed  Article  CAS  Google Scholar 

  2. Nishiyama T. Analgesic effects of systemic midazolam: comparison with intrathecal administration. Can J Anaesth. 2006;53:1004–1009.

    PubMed  Article  Google Scholar 

  3. Serrao JM, Marks RL, Morley SJ, Goodchild CS. Intrathecal midazolam for the treatment of chronic mechanical low back pain: a controlled comparison with epidural steroid in a pilot study. Pain. 1992;48:5–12.

    PubMed  Article  CAS  Google Scholar 

  4. Nishiyama T, Yokoyama T, Hanaoka K. Midazolam improves postoperative epidural analgesia with continuous infusion of local anaesthetics. Can J Anaesth. 1998;45:551–555.

    PubMed  Article  CAS  Google Scholar 

  5. Molinero MT, Del Rio J. Substance P, nicotinic acetylcholine receptors and antinociception in the rat. Neuropharmacology. 1987;26:1715–1720.

    PubMed  Article  CAS  Google Scholar 

  6. Lawand NB, Lu Y, Westlund KN. Nicotinic cholinergic receptors: potential targets for inflammatory pain relief. Pain. 1990;80:291–299.

    Article  Google Scholar 

  7. Phan DV, Doda M, Bite A, Gyorgy I. Antinociceptive activity of nicotine. Acta Physiol Acad Sci Hung. 1973;1:85–93.

    Google Scholar 

  8. Sullivan JP, Bannon AW. Epibatidine: pharmacological properties of a novel nicotinic acetylcholine receptor agonist and analgesic agent. CNS Drugs. 1996;2:21–39.

    Article  CAS  Google Scholar 

  9. Nishiyama T, Gyermek L, Trudell ML, Hanaoka K. Spinally mediated analgesia and receptor binding affinity of epibatidine analogs. Eur J Pharmacol. 2003;470:27–31.

    PubMed  Article  CAS  Google Scholar 

  10. Bonhaus AW, Bley KR, Broka CA, Fontana DJ, Leung E, Lewis R, Shieh A, Wong EH. Characterization of the electrophysiological, biochemical and behavioral actions of epibatidine. J Pharmacol Exp Ther. 1995;272:1199–1203.

    PubMed  CAS  Google Scholar 

  11. Tallarida RJ, Porreca F, Cowan A. Statistical analysis of drug—drug and site-site interactions with isobologram. Life Sci. 1989;46:947–961.

    Article  Google Scholar 

  12. Kohno T, Wakai A, Ataka T, Ikoma M, Yamakura T, Baba H. Actions of midazolam on excitatory transmission in dorsal horn neurons of adult rat spinal cord. Anesthesiology. 2006;104:338–343.

    PubMed  Article  CAS  Google Scholar 

  13. Rudomin P. Primary afferent depolarization produced in A delta and C fibres by glutamate spillover? New ways to look at old things. J Physiol. 2000;528:1.

    PubMed  Article  CAS  Google Scholar 

  14. Clavier N, Lombard MC, Besson JM. Benzodiazepines and pain: effects of midazolam on the activities of nociceptive non-specific dorsal horn neurons in the rat spinal cord. Pain. 1992;48:61–71.

    PubMed  Article  CAS  Google Scholar 

  15. Rogers DT, Iwamoto ET. Multiple spinal mediators in parenteral nicotine-induced antinociception. J Pharmacol Exp Ther. 1993;267:341–349.

    PubMed  CAS  Google Scholar 

  16. Gillberg PG, d’Argy R, Aquilonius SM. Autoradiographic distribution of [3H] acetylcholine binding sites in the cervical spinal cord of man and some other species. Neurosci Lett. 1988;90:197–202.

    PubMed  Article  CAS  Google Scholar 

  17. Laing I, Todd AJ, Heizmann CW, Schmidt HH. Subpopulations of GABAergic neurons in laminae I–III of rat spinal dorsal horn defined by coexistence with classical transmitters, peptides, nitric oxide synthase or parvalbumin. Neuroscience. 1994;61:159–166.

    Article  Google Scholar 

  18. Todd AJ. Immunohistochemical evidence that acetylcholine and glycine exist in different populations of GABAergic neurons in lamina III of rat spinal dorsal horn. Neuroscience. 1991;44:741–746.

    PubMed  Article  CAS  Google Scholar 

  19. Curzon P, Nikkel AL, Bannon AW, Arneric SP, Decker MW. Differences between the antinociceptive effects of the cholinergic channel activators A-85380 and (±)-epibatidine in rats. J Pharmacol Exp Ther. 1998;287:847–853.

    PubMed  CAS  Google Scholar 

  20. Flores CM, Wilson SG, Mogil JM. Pharmacogenetic variability in neuronal nicotinic receptor-mediated antinociception. Pharmacogenetics. 1999;9:619–625.

    PubMed  Article  CAS  Google Scholar 

  21. Badio B, Daly JW. Epibatidine, a potent analgesic and nicotinic agonist. Mol Pharmacol. 1994;45:563–569.

    PubMed  CAS  Google Scholar 

  22. Rao TS, Correa LD, Reid RT, Lloyd GK. Evaluation of antinociceptive effects of neuronal nicotinic acetylcholine receptor (nAChR) ligands in the rat tail-flick assay. Neuropharmacology. 1996;35:393–405.

    PubMed  Article  CAS  Google Scholar 

  23. Rupniak NMJ, Patel S, Marwood R, Webb J, Traynor JR, Elliott J, Freedman SB, Fletcher SR, Hill RG. Antinociceptive and toxic effects of (+)-epibatidine oxalate attributable to nicotinic agonist activity. Br J Pharmacol. 1994;113:1487–1493.

    PubMed  CAS  Google Scholar 

  24. Sullivan JP, Decker MW, Brioni JD, Donnelly-Roberts D, Anderson DJ, Kang CH, Adams P, Piattoni-Kaplan M, Buckley MJ. (±)-Epibatidine elicits a diversity of in vitro and in vivo effects mediated by nicotinic acetylcholine receptors. J Pharmacol Exp Ther. 1994;271:624–631.

    PubMed  CAS  Google Scholar 

  25. Advokat C, Rutherford D. Selective antinociceptive effect of excitatory amino acid antagonists in intact and acute spinal rats. Pharmacol Biochem Behav. 1995;51:855–860.

    PubMed  Article  CAS  Google Scholar 

  26. Khan IM, Yaksh TL, Taylor P. Epibatidine binding sites and activity in the spinal cord. Brain Res. 1997;753:269–282.

    PubMed  Article  CAS  Google Scholar 

  27. Puig S, Sorkin LS. Formalin-evoked activity in identified primary afferent fibres: systemic lidocaine suppresses phase 2 activity. Pain. 1996;64:345–357.

    PubMed  Article  CAS  Google Scholar 

  28. Li J, Simone DA, Larson A. Windup leads to characteristics of central sensitization. Pain. 1999;79:75–82.

    PubMed  Article  CAS  Google Scholar 

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Author information

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

Authors
  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

Key words

  • Antinociception
  • Gamma-aminobutyric acidA receptor
  • Nicotinic cholinergic receptor
  • Spinal cord