title: Cysteine protease inhibitors suppress the development of tolerance to morphine antinociception.
abstract: The effects of various protease inhibitors on the development of antinociceptive tolerance to morphine were examined in mice. Intrathecal (i.t.) administration of morphine (0.01-1 nmol) produced a dose-dependent and significant antinociceptive effect in the 0.5% formalin test. When the doses of morphine (mg/kg, s.c. per injection) were given as pretreatment twice daily for two days [first day (30) and second day (60)], i.t. administration of morphine (0.1 nmol) was inactive due to antinociceptive tolerance on the third day. Tolerance to i.t. morphine was significantly suppressed by the i.t. injection of N-ethylmaleimide or Boc-Tyr-Gly-NHO-Bz, inhibitors of cysteine proteases involved in dynorphin degradation, as well as by dynorphin A, dynorphin B and (-) U-50,488, a selective kappa-opioid receptor agonist. On the other hand, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, lisinopril, an angiotensin-converting enzyme inhibitor, and phenylmethanesulfonyl fluoride, a serine protease inhibitor, were inactive. These results suggest that cysteine protease inhibitors suppress the development of morphine tolerance presumably through the inhibition of dynorphin degradation.
authors.affiliation: Department of Pharmacology, Tohoku Pharmaceutical University, Sendai, Japan. koichi@tohoku-pharm.ac.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Tan-No
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shimoda
authors.forename: Mai
authors.initials: M
authors.lastname: Sugawara
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakagawasai
authors.forename: Fukie
authors.initials: F
authors.lastname: Niijima
authors.forename: Hiromi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Seiichi
authors.initials: S
authors.lastname: Furuta
authors.forename: Takumi
authors.initials: T
authors.lastname: Sato
authors.forename: Susumu
authors.initials: S
authors.lastname: Satoh
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Arai
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kotlinska
authors.forename: Jerzy
authors.initials: J
authors.lastname: Silberring
authors.forename: Lars
authors.initials: L
authors.lastname: Terenius
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tadano
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004361:Drug Tolerance / Q000502:physiology*; D004399:Dynorphins / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D005557:Formaldehyde; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D015853:Cysteine Proteinase Inhibitors; D005557:Formaldehyde; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins; D009020:Morphine; D005033:Ethylmaleimide