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Antinociceptive Effect Produced by Intracerebroventricularly Administered Dynorphin A Is Potentiated by P-Hydroxymercuribenzoate or Phosphoramidon in the Mouse Formalin Test

Antinociceptive Effect Produced by Intracerebroventricularly Administered Dynorphin A Is Potentiated by P-Hydroxymercuribenzoate or Phosphoramidon in the Mouse Formalin Test

K Tan-No, K Ohshima, A Taira, M Inoue, F Niijima, O Nakagawasai, T Tadano, I Nylander, J Silberring, L Terenius, K Kisara

Brain Res. 2001 Feb 9;891(1-2):274-80.

PMID: 11164832

Abstract:

The antinociceptive effects of intracerebroventricularly (i.c.v.) administered dynorphin A, an endogenous agonist for kappa-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 kappa-opioid receptor antagonist, but not by naltrindole, a selective delta-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 delta-opioid receptor active fragments enkephalins which are formed from dynorphin A.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP329986-A	Phenylmethanesulfonyl fluoride solution		329-98-6	Price

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