[Met5]enkephalin-Arg-Gly-Leu-induced antinociception is greatly increased by peptidase inhibitors

Previous in vitro studies showed that the degradation of [Met(5)]enkephalin-Arg-Gly-Leu by cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors: amastatin, captopril and phosphoramidon. The present investigations showed that the inhibitory effect of [Met(5)]enkephalin-Arg-Gly-Leu administered intra-third-ventricularly on the tail-flick response was increased more than 1000-fold by the intra-third-ventricular pretreatment of rats with three peptidase inhibitors. The inhibition produced by the enkephalin octapeptide in rats pretreated with any combination of two peptidase inhibitors was significantly smaller than that in rats pretreated with three peptidase inhibitors, indicating that any residual single peptidase could inactivate significant amounts of the octapeptide. The present data, together with those obtained from previous studies, clearly show that three types of enzymes, amastatin-, captopril- and phosphoramidon-sensitive enzymes, play important roles in the inactivation of endogenous opioid penta- and octa-peptides administered intra-third-ventricularly to rats.