The enhancing effects of peptidase inhibitors on the antinociceptive action of [Met5]enkephalin-Arg6-Phe7 in rats.
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.
Takahashi
Shigeru
S
Department of Clinical Pharmacology, School of Medicine, Tokai University, Isehara 259-1193, Japan.
Jin
Xing Lu
XL
Kosaka
Kenya
K
Yoshikawa
Masanobu
M
Kobayashi
Hiroyuki
H
Oka
Tetsuo
T
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004744:Enkephalin, Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006020:Glycopeptides / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000700:Analgesics; D006020:Glycopeptides; D009292:Narcotic Antagonists; D010455:Peptides; D011480:Protease Inhibitors; D009270:Naloxone; D004744:Enkephalin, Methionine; C016977:amastatin; C027511:enkephalin-Met, Arg(6)-Phe(7)-; D002216:Captopril; C008890:phosphoramidon