Time course of the changes in central nitric oxide synthase activity following chronic treatment with morphine in the mouse: reversal by naltrexone

1. The time course of the effect of chronic administration of morphine on the activity of nitric oxide synthase (NOS) in the brain regions and spinal cord of the mouse was determined. The effect of naltrexone by itself on the NOS activity and that induced by morphine also were determined. 2. Male Swiss Webster mice were implanted subcutaneously with a pellet containing 25 mg of morphine free base for 4 days. Placebo pellet implanted mice served as controls. 3. Twenty-four hours after treatment with morphine, NOS activity decreased in the cerebellum, midbrain, cortex and remainder of the brain as well as in the spinal cord. Forty-eight and 72 hr after the treatment with morphine, NOS activity increased in the cerebellum and cortex, but no change was observed in the other brain regions and spinal cord. Twenty-four hours after morphine pellet removal (withdrawal), NOS activity in all brain regions and the spinal cord has returned to normal. 4. Implantation of a pellet containing 10 mg of naltrexone did not alter NOS activity in any brain region or spinal cord for 24, 48 and 72 hr or 24 hr after removal of the pellet. 5. Implantation of a naltrexone pellet in conjunction with a morphine pellet blocked the changes in NOS activity in the brain region and spinal cord induced by morphine. 6. It is concluded that the initial decrease in NOS activity by morphine may be related to enhanced motor activity, whereas the increase in NOS activity in certain brain regions may be associated with tolerance-physical dependence development. Additionally, the changes in central NOS activity by morphine appear to be mediated by opioid receptors because they were blocked by concurrent treatment with naltrexone.