Hyperalgesia during withdrawal as a means of measuring the degree of dependence in morphine dependent rats

A modified flinch-jump procedure was used to detect changes in sensitivity to electric footshock in rats. In preliminary studies, dose-related increases in reaction thresholds (analgesia) were observed following intraperitoneal administration of 3, 6, or 9 mg/kg of morphine with the peak effect 60 min after injection. Analgesia and development of tolerance to the analgesic effects of morphine were detected 2–6 h and 12–24 h, respectively, after the subcutaneous (s.c.) implantation of a morphine pellet (75 mg base). In studies of withdrawal, rats made dependent by the s.c. implantation of morphine pellets showed significant decreases in reaction thresholds (hyperalgesia) and correlated decreases in body weight following removal of the pellet. The greatest changes during withdrawal occurred 12–36 h after pellet removal and the return of the reaction threshold to preremoval levels was associated with the return of normal diurnal fluctuation of body weight. Rats made dependent by s.c. administration of varying doses of morphine every 8 h for 11 days showed similar decreases in body weight and reaction threshold following abrupt cessation of drug injections. Animals receiving larger doses of morphine showed greater changes in the two measures, as well as a more rapid onset and more prolonged duration of effect. Peak effects were observed 48–60 h after the last injection of morphine. In another experiment, rats were made dependent to morphine by the pellet implantation procedure. Following i.p. administration of varying doses of naloxone, a morphine antagonist, there were dose-related decreases in reaction threshold and in body weight with the greatest decrease occurring 60–120 min after the injection. These investigations indicate that the hyperalgesia during withdrawal is a useful index of the degree of physical dependence in rats.