Suppressive effects by cysteine protease inhibitors on naloxone-precipitated withdrawal jumping in morphine-dependent mice

The effects of various protease inhibitors on naloxone-precipitated withdrawal jumping were examined in morphine-dependent mice. The doses of morphine were subcutaneously given twice daily for 2days (day 1, 30mg/kg; day 2, 60mg/kg). On day 3, naloxone (8mg/kg) was intraperitoneally administered 3h after final injection of morphine (60mg/kg), and the number of jumping was immediately recorded for 20min. Naloxone-precipitated withdrawal jumping was significantly suppressed by the intracerebroventricular administration of N-ethylmaleimide (0.5nmol) and Boc-Tyr-Gly-NHO-Bz (0.4nmol), inhibitors of cysteine proteases involved in dynorphin degradation, 5min before each morphine treatment during the induction phase, with none given on the test day, as well as by dynorphin A (62.5pmol) and dynorphin B (250pmol). However, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, and captopril, an angiotensin-converting enzyme inhibitor, caused no changes. The present results suggest that cysteine protease inhibitors suppress naloxone-precipitated withdrawal jumping in morphine-dependent mice, presumably through the inhibition of dynorphin degradation.