title: Increase in antinociceptive effect of [leu5]enkephalin after intrathecal administration of mixture of three peptidase inhibitors.
abstract: OBJECTIVE
  Previous in vitro studies have shown that the degradation of [Leu5]enkephalin during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors such as amastatin, captopril, and phosphoramidon. The present in vivo study was performed to examine the antinociceptive effect of [Leu5]enkephalin administered intrathecally under pretreatment with these three peptidase inhibitors.
  
  
  METHODS
  A tail-flick test was used to determine the nociceptive threshold after administration of [Leu5]enkephalin. The time-course profiles of the latency to flick the tail and the area under the time response curve were evaluated for the antinociceptive action of the drug.
  
  
  RESULTS
  The antinociceptive effect of [Leu5]enkephalin administered intrathecally on the tail-flick test was increased more than 100-fold under i.t. pretreatment with three peptidase inhibitors. The antinociceptive effect produced by [Leu5]enkephalin in rats pretreated with any single peptidase inhibitor increased antinociception compared to that with saline. The antinociceptive potency of [Leu5]enkephalin under pretreatment with any combination of two peptidase inhibitors was smaller than that in rats pretreated with three peptidase inhibitors together. These results indicate that any residual single peptidase inactivates significant amounts of [Leu5]enkephalin.
  
  
  CONCLUSIONS
  The present data, together with those of earlier studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play an important role in the inactivation of [Leu5]enkephalin administered intrathecally in rat.
authors.affiliation: Department of Anesthesiology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193 Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miura
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Shigeru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Junko
authors.initials: J
authors.lastname: Ajimi
authors.forename: Kenji
authors.initials: K
authors.lastname: Ito
authors.forename: Miho
authors.initials: M
authors.lastname: Ito
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000700:Analgesics; D000818:Animals; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004745:Enkephalins / Q000008:administration & dosage / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D059226:Nociceptive Pain / Q000188:drug therapy*; D017288:Pain Threshold / Q000187:drug effects*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D004338:Drug Combinations; D004745:Enkephalins; D006020:Glycopeptides; D010455:Peptides; D011480:Protease Inhibitors; C016977:amastatin; D002216:Captopril; C008890:phosphoramidon