The development of tolerance to and of physical dependence on morphine following intraventricular injection in the rat.

cal Hazards, Faculty of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo. The mechanism of the development of tolerance to and of physical dependence on morphine has been examined from a wide range of aspects. One of the approaches is to investigate the participation of brain biogenic amines in the actions of morphine. In 1954 Vogt (1) found a reduction of the content of hypothalamic norepinephrine after a subcutaneous morphine in the cat. Following her studies, some investigations were made on the change of the level of brain norepinephrine, dopamine and 5-hyroxytryptamine (5 HT) after either single or repeated administration of morphine. Recently it was found that the analgesic action of morphine was abolished when either catecholamine releasers such as reserpine and tetrabenazine (2), or a potent inhibitor of tyrosine hydroxylase, α-methyltyrosine (3), was given several hours before morphine in mice. This fact has suggested an important role played by catecholamines in the analgesic action of morphine. This suggestion has been further supported by the observation that the abstinence symptoms manifested by nalorphine in morphinized rats is deteriorated by a pretreatment with α-methyltyrosine or disulfiram (4). The present study deals with the development of tolerance to analgesic action of mor phine and the change of brain norepinephrine content after intraventricular injection of morphine into the rat. The abstinence symptoms induced by levallorphan in the rat that received repeated intraventricular injections of morphine are also reported.