This thesis describes the synthetic routes investigated in order to prepare amino estratrienes as potential small molecule mimics of endogenous opioid peptides. 3-Hydroxy-17 a-aminoestra-1,3,5(1 O)-triene was prepared from estra-1,3,5 (1 0)-trien-3,17p-diol by formation of the sulphonate ester 3-benzyloxy-1713- mesyloxyestra-1,3,5(1 O)-triene, displacement of the mesylate ester group with azide anion to give 3-benzyloxy-17a-azidoestra-1,3,5(10)-triene, followed by catalytic hydrogenation. As an altemative to hydrogenation, the Staudinger reaction was performed on the 17 a-azide but gave 3-benzyloxy-17 a( diethylphosphoramido )estra-1,3,5(1 O)-triene. A key compound, 3-Benzyloxy·6-azidomethyl-17p-acetoxyestra-1,3,5(1 0),6- tetraene was obtained from 3,17P-dihydroxyestra-1,3,5(10)-triene in seven steps. The synthesis involved benzylic oxidation of 3,17p-diacetoxyestra-1,3,5(1 O)-triene with chromium trioxide-3,5-dimethyl pyrazole complex to give the key intermediate, 3-benzyloxy-17 p-hydroxyestra-1,3,5(1 0)-trien-6-one. Sulphur ylid methylene insertion at the p-face of the 6-keto derivative gave 3-benzyloxy-6-spiro -epoxy- 17p-hydroxyestra-1 ,3,5(1 O)-triene. Base promoted isomerisation of the 6-spiro -epoxide gave 3-benzyloxy-6-hydroxymethyl-17p-hydroxyestra-1,3,5(10),6- tetraene. The allylic alcohol was acetylated and the key compound obtained from palladium(O)-catalysed allylic azidation. Other alternative approaches involved regioselective nucleophilic ring opening with azide anion of the 6-spiro -epoxide to give 3-benzyloxy-6-hydroxy-6- azidomethyl-17P-hydroxyestra-1,3,5(10)-triene. Manganese (IV) oxidation of the allylic alcohol gave the allylic aldehyde and its oxime, 3-benzyloxy-6-carbaldoxime- 17p-hydroxyestra-1,3,5(10),6-tetraene was obtained upon treatment with hydroxylamine hydrochloride. 3,17P-Bis(tert-butyldimethylsiloxy)estra-1,3,5(1 O)-triene gave [,,6-3,1713- bis(terl-butyldimethylsilyloxy)estra-1,3,5(1 O)-triene ]-tricarbonylchromium upon treatment with chromium hexacarbonyl. However, subsequent benzylic activation at position 6 and treatment with various electrophiles was unsuccessful.

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It is generally accepted that the neurotransmitter, serotonin mediates morphine-produced analgesia, however, it is not clear whether this mediation occurs at brain or spinal cord serotonin receptors. An issue that has not often been considered is the differential role that serotonin receptor types may play in morphine-produced analgesia. Paul and Phillips (1986) observed that pirenperone, a serotonin antagonist with a preferential affinity for the S2 receptor, attenuates morphine-produced analgesia. This result is particularly interesting because there are reportedly no S2 receptors in the spinal cord. The purposes of this dissertation were: to confirm the finding of Paul and Phillips, to localize the S2 receptors that mediate the anti-analgesic effect of pirenperone, and to test the hypothesis that pirenperone may exert its anti-analgesic effect through alpha-adrenergic receptors. In each of five experiments, tail-flick latencies (the time that it takes for each rat to withdraw its tail from a 52 C water bath) were measured 0, 30, 60, 90, and 120 min after drug injection. In Experiment 1, the analgesic effect of 10 mg/kg of morphine sulphate was challenged with 0.08, 0.16, and 0.24 mg/kg of pirenperone. Each dose of pirenperone attenuated morphine-produced analgesia. Moreover, each dose of pirenperone produced hyperalgesia in rats receiving no morphine. In Experiment 2, morphine-produced analgesia was challenged with 1, 3, and 10 mg/kg of ketanserin HCI. Only the very high 10 mg/kg dose ofketanserin significantly attenuated morphine-produced analgesia. Because ketanserin is pharmacologically similar to pirenperone but does not readily enter the central nervous system, this result indicates that central S2 receptors mediate the anti-analgesic effect of pirenperone and ketanserin. A third experiment demonstrated that 10 mg/kg of ketanserin did not block the analgesia produced by ketamine. Ketamine is thought to produce analgesia by a different mechanism than morphine. Thus, the attenuation of analgesia by S2 receptor blockers is not a general phenomenon, and it may be specific to morphine-produced analgesia and other analgesics that act on this system. Experiment 4 was designed to assess whether it is S2 receptors in the brain or in the spinal cord that mediate the anti-analgesic effect of S2 receptor blockade. The analgesic effect of morphine on tail-flick latencies was challenged with pirenperone in rats with spinal cords transected at the lower thoracic level and in sham-surgery comparison rats. Pirenperone attenuated morphine-produced analgesia in the sham-surgery group but not in the rats with transected spinal cords. These results indicate that brain S2 receptors mediate the attenuation of morphine-produced analgesia by pirenperone. In the fifth and final experiment, morphine-produced analgesia was challenged with 10 mg/kg of LY53857. LY53857 is an S2 antagonist which unlike pirenperone and ketanserin has no action at alpha-adrenergic receptors. Like pirenperone and ketanserin, LY53857 attenuated morphine-produced analgesia. This result supports the view that S2 receptorsmediate the anti-analgesic effects of pirenperone and ketanserin. Together, the results of these five experiments indicate that S2 receptors in the brain are important for opioid-mediated analgesia. This conclusion challenges the widely held view that only spinal cord serotonin receptors mediate morphine-produced analgesia. / Arts, Faculty of / Psychology, Department of / Graduate

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A blind, placebo–controlled clinical trial was performed to evaluate the postoperative analgesic effect of topically administered, intraoperative, epidural morphine (Duramorph™) and intramuscular infiltration of the incision site with bupivacaine prior to closure of the skin in dogs undergoing hemilaminectomy for Hansen type I Intervertebral Disk Disease (IVDD). Thirty-three dogs were randomly allocated into four treatment groups: epidural Duramorph™ with incisional bupivacaine (DUR/BUP), epidural saline with incisional bupivacaine (SAL/BUP), epidural Duramorph™ with incisional saline (DUR/SAL), and epidural saline with incisional saline (SAL/SAL). All dogs were premedicated with a standard protocol and were anesthetized with propofol and isoflurane. After surgery, scores were assigned using a visual analog scale (VAS) for both pain and sedation and a composite pain scale (CPS). In addition, a von Frey anesthesiometer was used to determine pain thresholds at 1 cm and 3 cm from the surgical incision line (primary hyperalgesia) as well as on the lateral aspect of the stifle (secondary hyperalgesia). Assessments were carried out at fixed intervals over the 48 hour postoperative period. Significant differences were found between those groups treated with the epidural Duramorph™ and those that received epidural saline. Those dogs in the DUR/BUP and DUR/SAL groups exhibited lower von Frey pain thresholds and higher VAS and CPS scores than the SAL/BUP and SAL/SAL groups. The administration of bupivacaine had no significant effect on any measured outcome. The authors conclude that topically administered epidural Duramorph™ and intramuscular incisional bupivacaine do not enhance analgesia following hemilaminectomy in the dog. / Master of Science

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O objetivo deste estudo foi o de comparar o emprego do tramadol, por via epidural ou sistêmica, com a morfina por via epidural, para controle da dor pós-operatória em cadelas submetidas à ovariohisterectomia, assim como determinar a ação dos agentes sobre o sistema cardiorespiratório e ocorrência de efeitos adversos. Para tanto, foram utilizadas 40 cadelas, distribuídas, aleatoriamente, em 4 grupos de 10 animais cada. O grupo 1 recebeu 2 /kg de tramadol por via epidural, o grupo 2 recebeu 2 mg/kg de tramadol por via intramuscular, o grupo 3 foi tratado com 0,1 mg/kg de morfina por via epidural e o grupo 4, determinado como controle, recebeu solução salina. Os fármacos foram administrados 30 minutos antes da indução anestésica, sendo o estudo caracterizado como prospectivo, clínico, tipo cego. Os animais foram pré-medicados com acepromazina, a indução anestésica realizada com propofol e o isofluorano foi empregado para manutenção da anestesia. As variáveis mensuradas foram: analgesia, sedação, freqüências cardíaca e respiratória, pressão arterial, concentração de isofluorano e dióxido de carbono no ar expirado, saturação periférica da oxihemoglobina, pH e gases sangüíneos, cortisol sérico e catecolaminas plasmáticas. Os animais foram avaliados por período de 24 horas após administração do fármaco analgésico. Os resultados foram submetidos à análise de variância, onde valores de P<0,05 foram considerados significantes. Não houve diferença entre os tratamentos com relação aos parâmetros de oxigenação, ventilação e cardiovasculares com exceção da pressão diastólica, que no grupo tratado com morfina apresentou menor valor que os demais grupos 6 horas após a administração dos analgésicos. Este grupo apresentou ainda menores escores de dor em vários momentos de avaliação, além de diminuir o requerimento de isofluorano em relação aos demais grupos aos 10 minutos de anestesia e aos 30 minutos, em comparação com o grupo controle, e menor valor de cortisol sérico 2 horas após a administração do fármaco analgésico em comparação ao grupo tratado com tramadol intramuscular e controle. Os grupos tratados com morfina epidural e tramadol epidural apresentaram menores valores de epinefrina que o grupo que recebeu tramadol intramuscular 2 horas após administração do agente analgésico. Os animais tratados com morfina não necessitaram medicação resgate durante o decorrer do estudo. Com base nos resultados obtidos, pode-se concluir que o emprego do tramadol epidural em cães é técnica segura, livre de efeitos adversos no sistema cardiorespiratório, porém o tratamento com morfina epidural foi superior a este e aos demais grupos com relação à qualidade da analgesia, sem apresentar efeitos adversos importantes / The aim of this study was to compare epidural or systemic tramadol and morphine to control postoperative pain in bitches submitted to ovariohysterectomy and to determine the effects of treatments on cardio and respiratory systems as well as side effects. Forty female dogs were randomly divided into four groups. Group 1 received 2 mg/kg of epidural tramadol, group 2 received 2 mg/kg of intramuscular tramadol, group 3 received 0,1 mg/kg of epidural morphine and group 4 as the control group, received saline solution. Treatments were administered 30 minutes before the induction of anesthesia and study was a prospective blinded clinical trial. Animals were premedicated with acepromazine, and anesthesia was induced with propofol. Isoflurane was used for the maintenance of anesthesia. Variables measured were: analgesia and sedation, cardiac and respiratory rates, arterial blood pressure, end-tidal isoflurane and carbon dioxide, oxyhemoglobin saturation, plasma catecholamines, serum cortisol, pH and blood gases. Patients were monitored for 24 hours after the administration of the analgesic agents. Data were submitted to analysis of variance. Values of p <0,05 were considered significant. There were no differences between groups with regard to oxygenation, ventilation and cardiovascular variables except for diastolic blood pressure which showed lower values in the morphine-treated group compared to other groups at six hours of evaluation, as well as lower pain scores at several evaluation moments. Rescue analgesia was not needed in the morphine group and the isoflurane concentration was significantly lower in relation to the other groups at 10 minutes of anesthesia, and at 30 minutes of anesthesia in relation to the control group. The epidural morphine group showed lower cortisol value at 2-hour evaluation as compared to intramuscular tramadol and control groups. The epidural tramadol and morphine groups had lower epinephrine value than intramuscular tramadol group. Based on the results of this study it can be concluded that epidural tramadol is a safe analgesia technique for dogs, free of undesirable effects, although epidural morphine was more effective than other groups without side effects