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Potentiation of [Met5]enkephalin-induced antinociception by mixture of three peptidase inhibitors in rat

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Abstract

Purpose

Previous in vitro studies have shown that degradation of opioid peptides during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), namely, amastatin, captopril, and phosphoramidon. In the present in vivo study, we evaluate the effects of intrathecal administration of these PIs on antinociception by [Met5]enkephalin (ME) or PIs themselves.

Methods

Drugs were administered into the thoracolumbar level of the spinal cord in the intrathecal space in rat. Induction of antinociception was measured by the tail immersion assay, with 55 °C as the nociceptive stimulus. Effects of PIs on antinociception were evaluated by dose–response study (ME, 1–20 nmol; PIs, 1–20 nmol each), by comparison of differences among two combinations of PIs (amastatin and captopril; captopril and phosphoramidon; amastatin and phosphoramidon) and three PIs (amastatin, captopril, and phosphoramidon), and by using opioid receptor selective antagonists.

Results

Intrathecal administration of ME with these three PIs or PIs alone significantly and dose dependently increased antinociception in a μ- and δ-opioid receptor antagonist-reversible manner; moreover, the degree of antinociception with a combination of any two of these was less than that with all three, indicating that any residual single peptidase could inactivate significant amounts of ME.

Conclusion

The present data, together with those of earlier studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play an important role in inactivation of opioid peptides at the spinal level.

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Acknowledgments

The authors thank Professor Jeremy Williams, Tokyo Medical University, for his assistance with the English of the manuscript.

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Authors and Affiliations

  1. Department of Anesthesiology, School of Medicine, Tokai University, Isehara, 259-1143, Japan

    Tomohiko Murata, Mariko Watanabe & Toshiyasu Suzuki

  2. Department of Clinical Pharmacology, School of Medicine, Tokai University, Isehara, 259-1143, Japan

    Masanobu Yoshikawa, Shigeru Takahashi & Hiroyuki Kobayashi

  3. Department of Pharmacology, Tokyo Dental College, Masago, Chiba, 261-8502, Japan

    Mitsuru Kawaguchi

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  1. Tomohiko Murata
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Correspondence to Masanobu Yoshikawa.

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Murata, T., Yoshikawa, M., Watanabe, M. et al. Potentiation of [Met5]enkephalin-induced antinociception by mixture of three peptidase inhibitors in rat. J Anesth 28, 708–715 (2014). https://doi.org/10.1007/s00540-014-1819-5

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  • DOI: https://doi.org/10.1007/s00540-014-1819-5

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