Morphine analgesia without development of tolerance in reserpinized mice

The relationship between the brain monoaminergic mechanism and morphine tolerance was examined in reserpinized mice. In parallel with the reduction of brain monoamine content, the analgesic effect of morphine was reduced in reserpinized animals. At the peak of the reserpine effect, 24 hr after a single dose of 2.5 mg/kg reserpine, i.p., the analgesic effect of morphine was lowered to about 45% of that in naive animals; and 5 days after reserpine treatment, it recovered to about 60% of the control activity. In these animals, the lowered effect of morphine was maintained at the same range during 6 daily repetitions, and the development of tolerance was suppressed. When daily morphine injection was started from 10 days after reserpine treatment, at the time when the brain level of monoamines was still reduced to 60 to 80% of the control, tolerance developed as rapidly as in control animals. On the other hand, daily treatment with a small dose of reserpine, 0.1 mg/kg, neither affected the brain level of norepinephrine and dopamine nor modified morphine analgesia, but completely blocked the development of tolerance. These results may suggest that suppression of the development of tolerance to morphine analgesia is not attributed to the reduction of brain norepinephrine and dopamine by reserpine. Morphine analgesia without development of tolerance in reserpinized mice may indicate the dissociation of the analgesic effect from tolerance liability.