Inhibition of dynorphin-converting enzymes prolongs the antinociceptive effect of intrathecally administered dynorphin in the mouse formalin test

Koichi Tan-No, Aki Taira, Tsukasa Sakurada, Makoto Inoue, Shinobu Sakurada, Takeshi Tadano, Takumi Sato, Chikai Sakurada, Ingrid Nylander, Jerzy Silberring, Lars Terenius, Kensuke Kisara

Research output: Contribution to journalArticlepeer-review

Abstract

The effects of peptidase inhibitors on the antinociception induced by intrathecally (i.t.) administered dynorphin A and dynorphin B in the mouse formalin test were examined. When administered i.t. 5 min before the injection of 0.5% formalin solution into the dorsal surface of a hindpaw, dynorphin A (0.5-2 nmol) and dynorphin B (2-8 nmol) produced a dose-dependent and significant reduction of the paw-licking response. Dynorphin A (2 nmol) and dynorphin B (8 nmol)-induced antinociception disappeared completely within 90 min and 60 min, respectively. p-Hydroxymercuribenzoate, a cysteine proteinase inhibitor, and phosphoramidon, an endopeptidase 24.11 inhibitor simultaneously administered with dynorphin A or dynorphin B, significantly prolonged antinociception induced by both dynorphins. However, captopril, an angiotensin-converting enzyme inhibitor, bestatin (a general aminopeptidase inhibitor) and a serine proteinase inhibitor phenylmethanesulfonyl fluoride, were inactive. Dynorphin-converting enzyme(s) transform dynorphin-related peptides to [Leu5]enkephalin and [Leu5]enkephalin-Arg6. Neither [Leu5]enkephalin nor [Leu5]enkephalin-Arg6, even at high dose (10 nmol), produced any antinociceptive effect. However, [Leu5]enkephalin-Arg6, but not [Leu5]enkephalin, produced a significant antinociceptive effect when co-administered with phosphoramidon. Therefore, the prolongation of the antinociception induced by both dynorphins in the presence of phosphoramidon, may be due to the inhibition of [Leu5]enkephalin-Arg6 degradation. The present results indicate that dynorphin-converting enzyme(s) may be important enzyme(s) responsible for terminating dynorphin-A- and dynorphin-B-induced antinociception at the spinal cord level in mice.

Original languageEnglish (US)
Pages (from-to)61-67
Number of pages7
JournalEuropean Journal of Pharmacology
Volume314
Issue number1-2
DOIs
StatePublished - Oct 24 1996
Externally publishedYes

Keywords

  • dynorphin A
  • dynorphin B
  • dynorphin-converting enzyme
  • formalin test
  • intrathecal administration
  • mouse
  • peptidohydrolase

ASJC Scopus subject areas

  • Pharmacology

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