Pharmacodynamics and kinetics of loss of tolerance and physical dependence on morphine induced by pellet implantation in the rat.

Abstract

The decay characteristics of tolerance and physical dependence on morphine induced by a pellet implantation procedure were determined in male Sprague-Dawley rats. Rats were implanted subcutaneously with 6 morphine pellets during a 7-day period. The pellets were removed, and at various times thereafter tolerance to the analgesic and hyperthermic effects of morphine was measured by determining the response in rats implanted with morphine and placebo pellets. Similarly, the physical dependence was assessed by monitoring withdrawal signs following an injection of naloxone. A high degree of tolerance developed to the analgesic and hyperthermic effects of morphine. Similarly, a high degree of physical dependence also developed as evidenced by a high incidence of jumping response, teeth chattering and production of fecal boli induced by injections of naloxone. In addition, loss of body weight and body temperature also occurred. The analgesic and hyperthermic response to morphine recovered very gradually. There was no significant difference in the analgesic and hyperthermic responses to morphine on day 4 after the pellet removal in rats implanted with morphine and placebo pellets. The decay of tolerance was linear with time for the analgesic effect (r = 0.98) and for the hyperthermic effect (r = 0.93). The change in symptoms of physical dependence on morphine with time depended on the specific symptom monitored. The average number of jumps and teeth chattering decreased with time in a linear fashion with r values of 0.98 and 0.99, respectively. However, the number of fecal boli and wet dog shakes increased linearly with time (r = 0.97). The recovery of loss of body weight was also linear with time. Thus, it is clear that fecal boli and wet dog shakes, which increase in number as the dependence decays, are signs of a low degree of dependence. The results suggest that different central or peripheral mechanisms may be operating in different withdrawal symptoms. These studies may prove to be useful when studying the mechanisms involved in the induction and reversibility of tolerance and dependence processes, and in long-term effects of opiates at a time when the tolerance and physical dependence is no longer evident.