Antinociceptive effect produced by intracerebroventricularly administered dynorphin A is potentiated by p-hydroxymercuribenzoate or phosphoramidon in the mouse formalin test

Koichi Tan-No, Kiyoshi Ohshima, Aki Taira, Makoto Inoue, Fukie Niijima, Osamu Nakagawasai, Takeshi Tadano, Ingrid Nylander, Jerzy Silberring, Lars Terenius, Kensuke Kisara

Research output: Contribution to journalArticlepeer-review

Abstract

The antinociceptive effects of intracerebroventricularly (i.c.v.) administered dynorphin A, an endogenous agonist for κ-opioid receptors, in combination with various protease inhibitors were examined using the mouse formalin test in order to clarify the nature of the proteases involved in the degradation of dynorphin A in the mouse brain. When administered i.c.v. 15 min before the injection of 2% formalin solution into the dorsal surface of a hindpaw, 1-4 nmol dynorphin A produced a dose-dependent reduction of the nociceptive behavioral response consisting of licking and biting of the injected paw during both the first (0-5 min) and second (10-30 min) phases. When co-administered with p-hydroxymercuribenzoate (PHMB), a cysteine protease inhibitor, dynorphin A at the subthreshold dose of 0.5 nmol significantly produced an antinociceptive effect during the second phase. This effect was significantly antagonized by nor-binaltorphimine, a selective κ-opioid receptor antagonist, but not by naltrindole, a selective δ-opioid receptor antagonist. At the same dose of 0.5 nmol, dynorphin A in combination with phosphoramidon, an endopeptidase 24.11 inhibitor, produced a significant antinociceptive effect during both phases. The antinociceptive effect was significantly antagonized by naltrindole, but not by nor-binaltorphimine. Phenylmethanesulfonyl fluoride (PMSF), a serine protease inhibitor, bestatin, a general aminopeptidase inhibitor, and captopril, an angiotensin-converting enzyme inhibitor, were all inactive. The degradation of dynorphin A by mouse brain extracts in vitro was significantly inhibited only by the cysteine protease inhibitors PHMB and N-ethylmaleimide, but not by PMSF, phosphoramidon, bestatin or captopril. The present results indicate that cysteine proteases as well as endopeptidase 24.11 are involved in two steps in the degradation of dynorphin A in the mouse brain, and that phosphoramidon inhibits the degradation of intermediary δ-opioid receptor active fragments enkephalins which are formed from dynorphin A.

Original languageEnglish (US)
Pages (from-to)274-280
Number of pages7
JournalBrain Research
Volume891
Issue number1-2
DOIs
StatePublished - Feb 9 2001
Externally publishedYes

Keywords

  • Cysteine protease
  • Dynorphin A
  • Endopeptidase 24.11
  • Formalin test
  • Intracerebroventricular administration
  • Mouse
  • Phosphoramidon
  • p-Hydroxymercuribenzoate

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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