Acceleration of cerebral noradrenaline turnover after morphine withdrawal and its retardation by acute morphine administration in rats

Summary To clarify the effects of withdrawal from chronic morphine treatment on cerebral noradrenaline (NA) turnover, we have measured the -methyl-p-tyrosine (MT)-induced depletion of NA in five brain areas of male Wistar rats given morphine twice daily for 40 or 60 days. After the last morphine dose (50 or 70 mg/kg) the rats were withdrawn for 1, 2 or 4 days. In order to study the development of tolerance a challenge dose of 10 mg/kg of morphine was given to some of the rats.Withdrawal of morphine accelerated the MT-induced NA depletion clearly in the hemispheres and the lower brain stem and slightly in the diencephalon. The acceleration was more pronounced in the brains of rats treated for 60 days than of those treated for 40 days. In the hemispheres the acceleration of NA depletion occurred at 1 and 2 days, in the diencephalon at 2 days, and in the lower brain stem at 2 and 4 days after morphine withdrawal. The most pronounced acceleration of NA depletion coincided with the maximum withdrawal-induced weight loss. The challenge dose of morphine clearly retarded the MT-induced NA depletion in the hemispheres of control rats treated chronically with saline. This retardation was even more pronounced in rats withdrawn from chronic morphine treatment for 1 or 2 days. The challenge dose slightly accelerated the MT-induced NA depletion in the lower brain stem of control rats. However, in rats withdrawn from chronic morphine treatment for 1 or 2 days the challenge dose instead of accelerating, clearly retarded, the NA depletion in the lower brain stem.Our results show that cerebral NA turnover is accelerated in rats withdrawn from morphine. The degree of this acceleration is proportional to the duration of chronic treatment. Tolerance does not seem to develop towards the NA release-inhibiting effect of morphine in the hemispheres, but develops towards the NA release-accelerating effect of morphine in the lower brain stem.