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UBC Theses and Dissertations

The role of type-2 serotonin receptors in morphine-produced analgesia Paul, Dennis John


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.

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