Abstract

Subcutaneous implantation of a 75-mg tablet of morphine base in the back of a mouse results in measurable tolerance and physical dependence within 12 to 24 hr. The rate and degree of tolerance development can be quantified by determining the median "analgetic" dose (AD5O) of morphine to inhibit the tail-flick response to thermal stimulus. The AD5O of morphine doubles after 1 day, and after 3 days of implantation generally increases 4- to 7-fold. Removal of the tablet after 3 days results in a time-dependent withdrawal syndrome which is characterized strikingly by an uncontrollable urge to jump. The response is maximal 4 to 10 hr after abrupt withdrawal and can be quantified by determining the percentage of animals that jump off a platform. Selective suppression of the response can be effected with morphine or any of its surrogates but not with other CNS agents. The morphine antagonist, naloxone, s.c., precipitates jumping within 5 min even in the presence of the tablet. The intensity of physical dependence at any interval after implantation can be quantified by estimating the ED5O of naloxone to precipitate the withdrawal jumping syndrome. Simultaneous assessment of morphine tolerance and physical dependence development and disappearance indicates a close relationship between the two syndromes and suggests that a common underlying mechanism may be involved.