Abstract. Previous in vitro studies have shown that the degradation of [Leu 5 ]enkephalin during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors: amastatin, captopril, and phosphoramidon. The present in vivo study shows that the inhibitory effect of [Leu 5 ]enkephalin administered intra-third-ventricularly on the tail-flick response was increased more than 500-fold by the intra-third-ventricular pretreatment with the three peptidase inhibitors. The antinociceptive effect produced by the [Leu 5 ]enkephalin in rats pretreated with any combination of two peptidase inhibitors was significantly smaller than that in rats pretreated with the three peptidase inhibitors, indicating that any residual single peptidase could inactivate significant amounts of the [Leu 5 ]enkephalin. The present data, together with those obtained from previous studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play important roles in the inactivation of short endogenous opioid peptides, such as penta-, hepta-, and octa-peptides, administered intra-third-ventricularly to rats.

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Abstract. Previous in vitro studies have shown that the degradation of [Met 5]enkephalin-Arg 6 -Phe 7 during incubation with cerebral membrane preparations is largely prevented by a mixture of three peptidase inhibitors: amastatin, captopril, and phosphoramidon. The present in vivo study shows that the inhibitory effect of [Met 5 ]enkephalin-Arg 6 -Phe 7 administered intra-thirdventricularly on the tail-flick response was increased more than 1000-fold by the intra-thirdventricular pretreatment with three peptidase inhibitors. ]enkephalin-Arg 6 -Gly 7 -Leu 8 , and dynorphin A (1-8), administered intra-third-ventricularly to rats.

The present data suggest that activation of NMDA receptors via glycine sites at the supraspinal level induces an antinociceptive effect on both acute and tonic pain.