Cysteine protease inhibitors suppress the development of tolerance to morphine antinociception.
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.
Tan-No
Koichi
K
Department of Pharmacology, Tohoku Pharmaceutical University, Sendai, Japan. koichi@tohoku-pharm.ac.jp
Shimoda
Masakazu
M
Sugawara
Mai
M
Nakagawasai
Osamu
O
Niijima
Fukie
F
Watanabe
Hiromi
H
Furuta
Seiichi
S
Sato
Takumi
T
Satoh
Susumu
S
Arai
Yuichiro
Y
Kotlinska
Jolanta
J
Silberring
Jerzy
J
Terenius
Lars
L
Tadano
Takeshi
T
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*
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