PHYSICAL-DEPENDENCE PRODUCED BY DIHYDROETORPHINE IN MICE

Using various administration schedules, the physical dependence produc ed by dihydroetorphine (DHE) was compared with that of morphine in mic e. Physical dependence, evaluated by naloxone-precipitated withdrawal signs, did not develop following daily treatment with DHE (10, 20, 100 and 1000 mu g/kg, i.p. or 30, 100 and 1000 ng/mouse, i.c.v.) for 6 d. However, 5 repeated injections of DHE (10 mu g/kg, i.p.) at 1 or 2 h intervals did produce physical dependence and the dependent state disa ppeared after 2 h. Accordingly, it was demonstrated that a sufficient degree of antinociceptive activity needed to be maintained, longer tha n several hours, for the development of physical dependence on DHE and that the duration of the dependent state was very short. In the singl e dose suppression test, a single dose of DHE completely suppressed th e natural withdrawal signs that appeared following abstinence in morph ine-dependent animals without reappearance of significant withdrawal s igns, indicating the suitability of DHE as a substitute for morphine. The characteristic properties of DHE, the extremely potent antinocicep tive effect and minimal dependence, indicate the separation of the ant inociceptive effect from dependence, and suggest that it may be possib le to develop a novel drug which may be safely used in clinical situat ions.