Tolerance and dependence after continuous morphine infusion from osmotic pumps measured by operant responding in rats

Food-deprived rats were trained to lever-press on a fixed interval 3-min schedule of food presentation. Using a cumulative dosing procedure, morphine and naltrexone were tested weekly for effects on rates of responding. A separate group of subjects was tested weekly for morphine analgesia using the tail-flick assay. Chronic morphine infusion (10 mg/kg/day, SC, from a 4-week osmotic pump) induced tolerance to the rate-decreasing and analgesic effects of morphine as demonstrated by a more than 4-fold increase in the morphine ED50s for both of these effects, relative to those of predependent rats. Physical dependence was evidenced in the operant procedure by increased sensitivity to the rate-decreasing effects of the opioid antagonist, naltrexone, such that the ED50 for naltrexone was 5000 times lower than it was in predependent animals. In addition, marked weight loss was observed over the 2-h naltrexone test session. The degree of tolerance was a function of both the length of chronic administration and of the maintenance dose and was of a similar magnitude for operant responding and analgesia. Further, the degree of tolerance and dependence was comparable to that observed in other studies that used different methods of chronic drug administration. Thus, osmotic pumps provide a convenient and effective alternative for chronic drug administration in behavioral studies.