Thesis (Ph. D.)--University of Wisconsin--Madison, 1955. / Typescript. Abstracted in Dissertation abstracts, v. 16 (1956) no. 2, p. 353. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 75-81).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1958. / Typescript. Abstracted in Dissertation abstracts, v. 18 (1958) no. 6, 2165-2166. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 70-78).

Thesis (M.S.)--University of Wisconsin--Madison, 1983. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 38-45).

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The mechanism of morphine analgesia is poorly understood. There is some anatomical, physiological, and behavioral evidence implicating the mesencephalic reticular formation in pain perception, and in morphine analgesia. The first part of this experiment was an attempt to determine, in rats, thresholds for escape from direct electrical stimulation of the reticular formation, and to determine the effects of morphine on these thresholds. Several investigators have hypothesized that the positive reinforcement systems in the brain may be involved in the production of the narcotic "high." It is also possible that these structures are related to the reinforcement-like aspects of narcotic addiction. The second part of this study was an attempt to determine positive reinforcement thresholds for direct electrical stimulation of the medial forebrain bundle (MFB), the major component of these reward pathways, and to determine the effects of morphine on these thresholds. Previous attempts to measure negative and positive reinforcement thresholds have, for the most part, employed variations of the classical method of limits. This method, however, suffers primarily from the fact that stimulus intensities are presented in a serial order. The method of constant stimuli has been found to be unreliable in addition to its theoretical shortcomings. The double staircase method, however, reduces, if not eliminates, the theoretical and practical problems of these other procedures, and was therefore used in the present study to measure intracranial reinforcement thresholds. Subjects were six male Fischer-derived albino rats. Three animals were implanted with electrodes in the reticular formation, and three with electrodes in the MFB. These electrodes were found to be negatively and positively reinforcing, respectively. The animals were then trained in the appropriate threshold determination task. Subjects were tested for several sessions until the change in threshold in response to saline injections was stable from session to session. The effects of various doses of morphine sulfate on these thresholds were then investigated. It was found that morphine increased the thresholds for escape from electrical stimulation of the reticular formation. These increases were dose-related, in that higher doses of the drug produced a greater increase in threshold. The results indicated that higher levels of stimulation were required to elicit escape responding after morphine than were required before drug administration, and therefore suggested that morphine depresses the excitability of the reticular formation in response to aversive stimulation. Thus, these results further implicate the reticular formation in the mediation of morphine analgesia. It was also found that morphine decreased the positive reinforcement thresholds for MFB stimulation. These decreases were dose-related in a U-shaped manner, that is, low to moderate doses decreased thresholds, while higher doses had no apparent effect on threshold. These results indicated that the animals were responding in order to receive levels of stimulation which were in fact lower than even pre-morphine detection levels, and therefore suggested that morphine increases the excitability of the positive reinforcement systems in the brain. It was concluded that this increase in excitability may be the neural mechanism involved in the production of the narcotic "high," and may also be related to the development of narcotic addiction. / 2031-01-01

No description available.

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).

Blast injuries represent a problem for civilian and military populations. The response to thoracic blast injury involves a reflex bradycardia, hypotension and apnoea. Casualties who have suffered a blast injury are likely to receive morphine as an early treatment, and may go on to suffer a haemorrhage, thus requiring fluid resuscitation. Aims of this thesis included determination of the effect of blast injury on the response to haemorrhage and whether these responses or their interaction are modified by morphine, and to compare the cardiovascular effects of early and late resuscitation with different solutions following blast injury and haemorrhage. Early cessation of the blast-induced apnoea is important if the patient is to adequately maintain arterial oxygen tensions and thus prevent the development of tissue hypoxia and a subsequent secondary inflammatory response. Therefore, the final aim of this thesis was to determine whether doxapram could shorten the duration of apnoea induced by thoracic blast. Results confirmed that the response to thoracic blast injury involves a bradycardia, hypotension and apnoea, and also a vasodilation and a reduction in blood flow in the femoral vascular bed. New findings from this thesis show that thoracic blast augments the bradycardia and hypotension seen during haemorrhage and that morphine attenuates this effect. The hypovolaemic blast-injured patient may be resuscitated early or late after haemorrhage with blood, 0.9% saline, colloids (modified gelatin and hydroxyethyl starch) hypertonic saline or hypertonic/hydroxyethyl starch. These fluids restored blood pressure and femoral blood flow to pre-haemorrhage levels for at least 30 minutes. However, resuscitation with hypertonic saline/de>ttran was shown to be deleterious following blast injury and haemorrhage as blood pressure and femoral blood flow was not maintained for longer than 5 minutes following resuscitation with this fluid. The blast-induced apnoea and hypotension can be significantly attenuated by doxapram immediately following blast injury. This respiratory stimulant may also result in an improvement in venfilation/perfusion matching in the lungs and thus better fissue oxygenation, as administration of doxapram resulted in an improvement in the indices of metabolic acidosis. The new information gained from the work covered by this thesis could potentially lead to better treatment of the blast-injured victim.

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).

Thesis--Ph. D., University of Hong Kong, 1986.

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.