The dose-response relation and tolerance pattern of morphine in the formalin test, an animal model of tonic pain, were shown to be similar to those observed clinically in man. Tolerance was negligible and there was a ceiling to amount of analgesia once the acute depressant effects of morphine abate. In contrast, in the tail-flick test marked tolerance was seen in which the dose-response curve was shifted towards higher doses. These differences suggest that the underlying neural mechanisms involved in morphine analgesia in the formalin and tail-flick tests are different. In confirmation, brainstem lesions in the raphe magnus and the caudal periventricular gray attenuated analgesia in the tail-flick test but had no effect on analgesia in the formalin test. Lesions of the median raphe and the pontine reticular formation potentiated the effects of morphine in the formalin test but not in the tail-flick test. No brainstem lesion site was found that attenuated analgesia in the formalin test.

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Thesis--University of Wisconsin--Madison. / Typescript. Vita. Includes bibliographical references (leaves 122-128).

Thesis (Ph. D.)--University of Pennsylvania, 1942. / Reproduced from type-written copy. Bibliography: p. [60-62].

Thesis (M.S.)--University of Wisconsin--Madison, 1980. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 49-57).

For years now, opium alkaloids and morphinans have been attractive synthetic targets for numerous organic chemists due to their important biological activity and interesting molecular architecture. Morphine is one of the most potent analgesic drugs used to alleviate severe pain. Our research group maintains a longstanding interest in tandem pericyclic reactions such as the oxy-Cope/Claisen/ene reaction cascade and their application to the total synthesis of complex natural products. Herein we report the ventures towards the formal synthesis of (+/-)-morphine based on the novel tandem oxy- Cope/Claisen/ene reaction developed in our laboratory. These three highly stereoselective pericyclic reactions occurring in a domino fashion generate the morphinan core structure after only 7 steps from commercially available material. The formal synthesis culminated in the production of a formal intermediate after a total of 18 linear steps, with an overall yield of 1.0%, successfully intersecting two previous syntheses of the alkaloids, namely the ones of Taber (2002) and Magnus (2009).

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The role of noradrenaline (NA) in the behavioural and pharmacological effects of morphine was evaluated in rats. Animals received specific injections of 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle (DB) resulting in selective depletion of telencephalic NA levels and increased levels of noradrenaline in the spinal cord and cerebellum. Employing changes in the hypoactive phase of morphine-induced locomotor activity as an index of tolerance development, it was observed that injection of 6-OHDA into the dorsal noradrenergic bundle resulted in a slower rate and a lesser degree of tolerance development to morphine. The effect of the DB-6-0HDA lesion on physical dependence was assessed by measuring naltrexone-induced withdrawal in lesioned and control animals who had received chronic morphine treatment. Results indicate that although NA is important in tolerance development, it does not mediate a dominant role in withdrawal, although behavioural evidence suggesting a secondary or modulatory role is presented. The interaction of amphetamine and morphine with the dopamine (DA) system was also assessed by studying the behavioural effects of amphetamine in animals following either acute or chronic morphine treatment. It was observed that amphetamine potentiated the spontaneous locomotor hyperactivity following both acute and chronic morphine treatment. The DB-6-OHDA lesion did not affect the locomotor potentiation of amphetamine in morphine pre-treated animals, and the hypothesis that another transmitter system mediates this effect, specifically DA, is discussed. / Medicine, Faculty of / Graduate

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