Cysteine protease inhibitors suppress the development of tolerance to morphine antinociception

• Published in: Neuropeptides (Edinburgh) Vol. 42; no. 3; pp. 239 - 244
• Main Authors: Tan-No, Koichi, Shimoda, Masakazu, Sugawara, Mai, Nakagawasai, Osamu, Niijima, Fukie, Watanabe, Hiromi, Furuta, Seiichi, Sato, Takumi, Satoh, Susumu, Arai, Yuichiro, Kotlinska, Jolanta, Silberring, Jerzy, Terenius, Lars, Tadano, Takeshi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.06.2008; Elsevier
• Subjects: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer - pharmacology; Advanced Basic Science; Analgesics; Analgesics, Opioid - pharmacology; Animals; Antinociceptive tolerance; Biological and medical sciences; Cysteine protease inhibitors; Cysteine Proteinase Inhibitors - pharmacology; Drug Tolerance - physiology; Dynorphins; Dynorphins - pharmacology; Endocrinology & Metabolism; Ethylmaleimide - pharmacology; Formaldehyde; Fundamental and applied biological sciences. Psychology; Injections, Spinal; Injections, Subcutaneous; Intrathecal injection; Male; Medical sciences; Medicin och hälsovetenskap; Mice; Morphine; Morphine - pharmacology; Mouse; Neuropharmacology; Pain Measurement - drug effects; Pharmacology. Drug treatments; Vertebrates: endocrinology; benzoyl; Cysteine protease inhibitors; Mouse; Boc; Bz; Dynorphins; Morphine; Intrathecal injection; tert-butyloxycarbonyl; Antinociceptive tolerance; Thiol; Cysteine; Rodentia; Tolerance; Opiates; Narcotic analgesic; Neuropeptide; Opioid peptide; Sulfur containing aminoacid; Vertebrata; Mammalia; Animal; Dynorphin; Development; Protease inhibitor
• ISSN: 0143-4179; 1532-2785
• DOI: 10.1016/j.npep.2008.03.003

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 κ-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.