Thesis (Ph. D.)--University of Virginia, 2007. / Includes bibliographical references. Also available online through Digital Dissertations.

Thesis (doctoral)--University of Copenhagen, 2007. / Thesis based on ten publications.

Thesis (M.S.) in Zoology--University of Maine, 2006. / Includes vita. Includes bibliographical references (leaves 33-36).

Thesis (Ph. D.)--Georgia State University, 2006. / Title from title screen. Donald H. Edwards, committee chair; Deborah J. Baro, co-chair; Charles D. Derby, Larry J. Young, committee members. Electronic text (182 p. : ill. (some col.)) : digital, PDF file. Description based on contents viewed May 21, 2007. Includes bibliographical references (p. 161-182).

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Acetaminophen and N,N-dimethylformamide (DMF) are compounds which are extremely toxic to the liver. Acetaminophen is a drug which is well known for its analgesic and antipyretic properties. However, the abuse potential of this agent as a non-narcotic analgesic in alcoholics is well known. It is also the leading cause of overdose in England. DMF toxicity results mainly from occupational exposure. At present there are no known reports of an antidote for DMF poisoning, while N-acetylcysteine, the antidote for acetaminophen poisoning, is known to produce adverse effects. The present study evaluates the potential of melatonin as an antidote for acetaminophen and DMF poisoning. This study also investigates the mechanism underlying acetaminophen addiction and abuse. Initial studies involved in vitro techniques in an attempt to remove the complexities of organ interactions. The photodegradation studies, using ultraviolet (UV) light, revealed that melatonin accelerates the rate of acetaminophen degradation in the presence of air, and reduces the rate of degradation in the presence of nitrogen. This study also revealed that melatonin is rapidly degraded in the presence of air, following UV irradiation. The effect of DMF on hydroxyl radical generation was also determined. DMF was shown to act as a free radical scavenger, rather that a generator of free radicals. The in vitro studies were followed by lipid peroxidation determination. DMF (0.4ml/kg and 0.8ml/kg) did not produce any significant increases in lipid peroxidation in the liver. Three different doses of acetaminophen (30mg/kg, 100mg/kg, and 500mg/kg) were administered to rats for seven days. Acetaminophen (500mg/kg) was shown to significantly increase (p<0.05) lipid peroxidation in the liver. Melatonin (2.5mg/kg) was not able to significantly reduce the damage. The lower doses of acetaminophen (30mg/kg and 100mg/kg) did not increase lipid peroxidation. Electron microscopy studies showed that DMF adversely affects the liver, and in particular, the endoplasmic reticulum. Co administration of melatonin (2.5mg/kg) was able to reduce the damage. Further experiments need to be performed before an accurate assessment can be made on the ability of melatonin as an antidote for DMF and acetaminophen poisoning. Several experiments were done in an attempt to uncover the biochemical mechanism underlying acetaminophen addiction and abuse. The first experiment targeted the liver enzyme tryptophan-2,3-dioxygenase (TDO). This enzyme is the major determinant of tryptophan levels in vivo. Acetaminophen administration (100mg/kg for three hours) was shown to significantly inhibit (p<0.05) the activity of TDO, indicating increased peripheral levels of tryptophan. This experiment was followed up with determination of brain serotonin and pineal melatonin. Brain serotonin was determined using the ELISA technique. Melatonin was estimated using this technique as well as with pineal organ culture. Acetaminophen administration (100mg/kg for three hours) significantly increased (p<0.05) brain serotonin levels. Using organ culture where exogenous (3H) tryptophan is metabolised to (3H) melatonin, acetaminophen (100mg/kg for three hours) was shown to significantly increase (p<0.05) pineal melatonin concentrations. However, the ELISA technique did not reveal any changes in endogenous pineal melatonin levels. The final experiment was the determination of urinary 5-hydroxyindole acetic acid (5- HIAA), the major metabolite of serotonin, following acetaminophen administration (100mg/kg for three hours). Acetaminophen was shown to significantly reduce 5-HIAA levels (p<0.05) suggesting reduced catabolism of serotonin. The findings of this study indicate that acetaminophen mimics the actions of an antidepressant. This compelling finding has important clinical implications, and needs to be examined further.

The monoamine uptake blocking agents, imipramine HC1 (5 mg/kg i.v.) and desipramine HC1 (4.8 mg/kg i.v.), and the monoamine oxidase inhibitor, pargyline HC1 (30 mg/kg i.v.) antagonized bulbospinal inhibition (BSI) of the monosynaptic reflex (MSR) in unanaesthetized cats decerebrated at the mid-collicular level. The effect of imipramine was quantitatively more on BSI of the quadriceps (QUAD)-MSR compared to that on BSI of the posterior biceps-semitendinosus (PBST)-MSR. Imipramine's action on this inhibition was also quantitatively greater compared to that of the equimolar dose of desipramine. Pretreatment of the animals with the tryptophan hydroxylase inhibitor, DL-p-chlorophenylalanine (p-CPA) (300 mg/kg i.p. for 3 consecutive days) completely eliminated the blocking action of imipramine. However, pretreatment of the animals with the tyrosine hydroxylase inhibitor, DL-α-methyl-p-tyrosine methyl ester HC1 (α-MPT) (126 mg/kg i.p. given 16 and 4 hours before the recording ) had no effect on imipramine's action. These findings strongly suggest that a 5-hydroxytryptamine (5-HT, serotonin) system antagonizes BSI of the MSR. They do not support the proposal of Clineschmidt and Anderson (1970) that the bulbospinal inhibitory pathway involves a 5-HT interneurone in the spinal cord. Imipramine HC1 (5 mg/kg i.v.) and pargyline HC1 (30 mg/kg i.v.) blocked recurrent inhibition (RI) of the MSR evoked by stimulation of a dorsal root. Imipramine blocked RI of the QUAD-MSR but had no effect on RI of the PBST-MSR. Pretreatment of the animals with either p-CPA or α-MPT prevented the blocking action of imipramine on RI. Application of a 'cold block' which potentiated RI of the QUAD-MSR also eliminated the blocking action of imipramine on this inhibition. These observations suggest that a supraspinal monoaminergic system which involves 5-HT and noradrenaline links has a tonic inhibitory effect on RI of the QUAD-MSR. / Pharmaceutical Sciences, Faculty of / Graduate

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