Pharmacological Study of Substance P and Dynorphin on the Spinal Regulation of Nociceptive Information

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The effects of protease inhibitors on the antinociception induced by intrathecally (i.t.) administered dynorphin (Dyn) in the mouse formalin test were examined. Both p-hydroxymercuribenzoate (PHMB), a cysteine protease inhibitor, and phosphoramidon, an endopeptidase 24.11 inhibitor, prolonged Dyn-induced antinociception. However, captopril, an angiotensin-converting enzyme inhibitor, bestatin (a general aminopeptidase inhibitor) and a serine protease inhibitor phenylmethanesulfonyl fluoride, were inactive. Neither [Leu^5] enkephalin (Leu-Enk) nor Leu-Enk-Arg^6, the products of Dyn by cysteine proteases, produced any antinociceptive effect. However, Leu-Enk-Arg^6, but not Leu-Enk, produced a significant antinociceptive effect when coadministered with phosphoramidon. Therefore, the prolongation of the antinociception induced by Dyn in the presence of phosphoramidon may be due to the inhibition of Leu-Enk-Arg^6 degradation. Moreover, the antinociceptive effect of i.t. administered PHMB was compared with that of phosphoramidon in the presence of bestatin in the mouse capsaicin test. Both PHMB and phosphoramidon/bestatin induced the antinociceptive effect. The antinociceptive effect induced by PHMB and phosphoramidon/bestatin was inhibited by nor-BNI,a selective kappa receptor antagonist, and naltrindole, a selective delta receptor antagonist, respectively. The present results indicate that cysteine proteases may be important enzymes in terminating Dyn-induced antinociception and the antinociceptive effect of PHMB and phosphoramidon/bestatin may be due to the inhibition of the degradation of endogenous Dyns and enkephalins, respectively.