EFFECT OF 1-PHENYL-3-(2-THIAZOLYL)-2-THIOUREA, A DOPAMINE -HYDROXYLASE INHIBITOR, ON MORPHINE ANALGESIA, TOLERANCE AND PHYSICAL DEPENDENCE

¹ Department of Pharmacology, School of Medicine, University of California, San Francisco, California

The administration of 1-phenyl-3-(2-thiazolyl)-2-thiourea (PTT) partially inhibited the development of tolerance to and physical dependence on morphine in the mouse. Reduction of tolerance development by PTT was evidenced by the decrease in the amount of morphine necessary to produce analgesia and the reduction in dependence by the increase in the amount of naloxone necessary to induce precipitated withdrawal jumping after morphine pellet implantation for 3 days. Further evidence regarding dependence development inhibition by PTT was indicated by a reduction in body weight loss which occurs after abrupt withdrawal of morphine from dependent animals. PTT potentiated morphine analgesia, but the effect could not be correlated with changes in brain levels of norepinephrine, dopamine, copper, serotonin, acetylcholine and choline nor with altered brain uptake of morphine. However, the inhibition of morphine tolerance and dependence development by PTT was accompanied by a decrease in brain serotonin turnover. Also the inhibition by PTT of naloxone-precipitated withdrawal jumping in dependent mice was accompanied by an elevation in brain acetylcholine and an inhibition of the sudden rise in dopamine that occurs during Precipitated withdrawal. The latter findngs are compatible with the conclusion that cholinergic-doparninergic pathways have a major participatory role in the withdrawal jumping syndrome.