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.
Subject(s)
Captopril/pharmacology , Enkephalin, Leucine/pharmacology , Glycopeptides/pharmacology , Pain/drug therapy , Peptides/pharmacology , Protease Inhibitors/pharmacology , Animals , Drug Synergism , Guinea Pigs , Ileum/drug effects , Ileum/physiology , Injections, Intraventricular , Male , Mice , Mice, Inbred ICR , Muscle Contraction/drug effects , Pain/physiopathology , Rats , Rats, Wistar , Vas Deferens/drug effects , Vas Deferens/physiologyABSTRACT
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-third-ventricularly on the tail-flick response was increased more than 1000-fold by the intra-third-ventricular pretreatment with three peptidase inhibitors. The antinociceptive effect produced by the [Met(5)]enkephalin-Arg(6)-Phe(7) 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 [Met(5)]enkephalin-Arg(6)-Phe(7). The present data, together with those obtained from previous studies, clearly show that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play important roles in the inactivation of endogenous opioid peptides, such as [Met(5)]enkephalin, [Met(5)]enkephalin-Arg(6)-Phe(7), [Met(5)]enkephalin-Arg(6)-Gly(7)-Leu(8), and dynorphin A (1-8), administered intra-third-ventricularly to rats.
Subject(s)
Analgesics/pharmacology , Enkephalin, Methionine/analogs & derivatives , Protease Inhibitors/pharmacology , Analgesics/administration & dosage , Animals , Captopril/administration & dosage , Captopril/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Enkephalin, Methionine/administration & dosage , Enkephalin, Methionine/pharmacology , Glycopeptides/administration & dosage , Glycopeptides/pharmacology , Injections, Intraventricular , Injections, Subcutaneous , Male , Naloxone/administration & dosage , Naloxone/pharmacology , Narcotic Antagonists/administration & dosage , Narcotic Antagonists/pharmacology , Pain/physiopathology , Pain/prevention & control , Pain Measurement/methods , Peptides/administration & dosage , Peptides/pharmacology , Protease Inhibitors/administration & dosage , Rats , Rats, WistarABSTRACT
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.
