POSSIBLE INVOLVEMENT OF THE TOTAL AMOUNT OF MORPHINE INFUSED IN THE DEVELOPMENT OF ACUTE MORPHINE-DEPENDENCE IN RATS

The severity of naloxone-precipitated withdrawal in rats infused intra venously with morphine at the rates of 2.5, 5 and 10 mg/kg/hr over var ious time periods was investigated. Plasma morphine concentration reac hed a constant and rate-dependent level at 1 hr after the start of mor phine infusion, and this level was maintained until the termination of infusion. Naloxone (2.0 mg/kg, s.c.) was challenged 18 hr after infus ion was stopped, and the withdrawal was evaluated by plasma corticoste rone (PCS) increase, diarrhea and body weight loss. The incidence of n aloxone-precipitated withdrawal signs was related to both the infusion rate and duration of morphine infusion. The duration of morphine infu sion (ET(50)) needed to elicit naloxone-precipitated PCS increase and diarrhea in 50% of the rats was inversely related to the morphine infu sion rates, but the total amount of infused morphine (EA(50)) that eli cited naloxone-precipitated withdrawals in 50% of rats was the same at all infusion rates. These results suggest that the total amount of mo rphine infused may play an important role in the development of acute physical dependence on morphine rendered by continuous intravenous mor phine infusion for 1-8 hr.