Morphine hyperalgesia: Contribution of opioid receptors, dosing regimen, and gonadal hormones.
Item
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Title
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Morphine hyperalgesia: Contribution of opioid receptors, dosing regimen, and gonadal hormones.
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Identifier
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AAI3296935
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identifier
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3296935
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Creator
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Juni, Aaron N.
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Contributor
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Adviser: Benjamin Kest
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Date
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2008
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience
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Abstract
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Hyperalgesia during morphine treatment is extensively conceptualized as a process that is mediated by opioid and NMDA receptors, and thought to be a causative factor in morphine analgesic tolerance. These assumptions were tested in mice assessed for nociceptive sensitivity on the tail-withdrawal test during continuous infusion of various morphine doses. Mice infused with the lowest morphine dose did not demonstrate any analgesia, but exhibited hyperalgesia that dissipated after 6 days. In contrast, the highest morphine dose elicited 2 days of analgesia followed by 10 days of hyperalgesia before resolution to baseline by Day 12. Acute exposure to NMDA receptor antagonists resulted in transient hyperalgesic reversal during both infusion paradigms, implicating NMDA receptor involvement in the maintenance of hyperalgesic states. Cross adaptation studies between the 2 doses and M3G, a primary morphine metabolite, implicated M3G in the mediation of low-dose hyperalgesia only. The lack of cross adaptation between the 2 infusion doses themselves, suggested their distinct mechanistic mediation.;Evidence for a relationship between analgesic tolerance and hyperalgesia was not found, as ED50 values derived from analgesia dose-response curves yielded significant differences between hyperalgesia and tolerance including magnitude, onset, and adaptation. Studies conducted under continuous opioid receptor blockade and with triple opioid receptor knockout mice, further suggested that prior analgesia is not a prerequisite for hyperalgesia, and that morphine hyperalgesia is a non-opioid receptor mediated process.;Although sex differences in nociception and several morphine related measures have previously been described, little is known about the impact of gender on morphine hyperalgesia. This dissertation thus also compared nociception in male and female mice during morphine infusion. In contrast to males, females did not adapt to hyperalgesia during low dose infusion, and hyperalgesia during high dose infusion was refractory to NMDA receptor antagonism. Ovariectomy, but not ovariectomy followed by estrogen infusion, abolished these qualitative sex differences.;The data indicate multiple mechanisms of morphine hyperalgesia, with utilization being at least partly dependent upon female sex hormones. Some of the conclusions arising from these findings are outside of current conceptualizations, yielding new insights into the clinical utility and physiological circuitry underlying morphine analgesic therapy.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
