Effects of morphine, in vitro and in vivo, on tyrosine hydroxylase activity in rat brain

The effect of morphine on the synthesis of catecholamines was determined in rat brain. In agreement with other studies, morphine produced a dose-dependent increase in the biosynthesis of the catecholamines. To assess whether morphine might enhance the synthesis of norepinephrine and dopamine by a direct chemical interaction with tyrosine hydroxylase, the rate-limiting step in their biosynthesis, the effects of the narcotic on the activity of the enzyme were determined in several regions of rat brain. Morphine, in vitro, from 10^-8 to 10^-2 M had no effect on the activity of tyrosine hydroxylase in any region examined. Moreover, morphine (10^-5 and 10^-3 M) had no effect on the apparent K_m of tyrosine hydroxylase for either substrate or cofactor (6-7-dimethyl-5, 6,7,8-tetrahydropterine). In addition, morphine (10^-5 and 10^-3 M) failed to block the inhibition of tyrosine hydroxylase, in vitro, by norepinephrine and dopamine in the hypothalamus and caudate respectively. The effects of morphine treatment, in vivo, on enzyme activity were also examined. The results of these studies indicated that acute injections of morphine had no effect on tyrosine hydroxylase activity, in vitro, indicating that the drug did not alter the level of an endogenous activator or inhibitor of tyrosine hydroxylase. Further studies indicated that development of tolerance to and physical dependence on morphine was not associated with an increase in the activity of brain tyrosine hydroxylase activity. The results of these studies suggest that morphine does not enhance the biosynthesis of catecholamines by a direct effect of tyrosine hydroxylase and that tolerance to the narcotic is not characterized by an induction of this enzyme.