In order to determine the possible contribution of altered distribution of morphine in the morphine tolerance process, the distribution of morphine was studied in brain regions and spinal cord, following its intravenous administration. Male Sprague-Dawley rats were made tolerant to morphine by implanting 6 morphine pellets, each containing 75 mg of morphine base, for 7 days. Seventy-two hours after the removal of the pellets, a time when serum morphine levels were negligible or absent and yet tolerance to the pharmacological effects of morphine was present, morphine (10 mg/kg, i.v.) was injected in placebo and morphine pellet implanted rats. At various times (5, 30, 60, 120 and 360 min) after the injection of morphine, brain regions (hypothalamus, cortex, hippocampus, midbrain, pons and medulla, striatum and amygdala), spinal cord and serum were collected. The level of morphine in the tissues was determined by using a highly sensitive and specific radioimmunoassay (RIA) method. Five minutes after morphine injection, the concentration of morphine was the highest in the hypothalamus and the lowest in amygdala. The concentration of morphine in hypothalamus, pons and medulla, hippocampus and midbrain of morphine tolerant rats was smaller than in placebo pellet implanted rats. The tissue to serum ratio of morphine in the hypothalamus, hippocampus, striatum, midbrain and cortex were also smaller in morphine tolerant than in non-tolerant rats. The concentration of morphine in brain regions with time did not exhibit linearity. At other time intervals like 30 and 60 min, the concentration of morphine in several brain regions and spinal cord was significantly higher in morphine tolerant than in non-tolerant rats.(ABSTRACT TRUNCATED AT 250 WORDS)