The effects of morphine on plasma corticosterone concentration in rats were studied using the drug-admixed food method. Morphine was mixed with the powder form of rat food in concentrations of 0.5 mg/g, 1 mg/g, and 2 mg/g of food. Plasma corticosterone concentration in rats treated with morphine-admixed food increased significantly, and the increment depended on the morphine concentration of drug-admixed food. The time course change of plasma corticosterone concentration in rats treated with morphine-admixed food (1 mg/g food) for 1 week was similar to that of non-treated rats without the concentration at 9:00. The plasma corticosterone concentration of morphine-treated rats at 9:00 was significantly increased in comparison with that of non-treated rats. Furthermore, the plasma corticosterone concentration after withdrawal in morphine-treated rats increased with time, and a significant increment in corticosterone was observed at 24 hr after the withdrawal. Naloxone, injected subcutaneously into morphine-dependent rats, significantly increased plasma corticosterone concentration. Increment of plasma corticosterone concentration in rats treated with morphine-admixed food for 3 or 4 weeks was significantly different from the non-treated group. The increment of plasma corticosterone concentration after the withdrawal was in a morphine treatment period-related manner. By these results, we suggest that tolerance to the increment action in plasma corticosterone concentration of morphine does not develop for at least 4 weeks using the drug-admixed food method, and the drug-admixed food method could induce morphine dependence without disturbance of the circadian rhythm in plasma corticosterone.