The role of medullary cholinergic and excitatory amino acid receptors mediating mesencephalic opioid antinociception.
Item
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Title
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The role of medullary cholinergic and excitatory amino acid receptors mediating mesencephalic opioid antinociception.
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Identifier
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AAI9924854
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identifier
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9924854
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Creator
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Spinella, Marcello.
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Contributor
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Adviser: Richard J. Bodnar
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Date
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1999
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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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Psychology, Physiological | Biology, Neuroscience | Health Sciences, Pharmacology
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Abstract
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Three experiments were performed to assess the respective roles of medullary cholinergic and excitatory amino acid receptors mediating mesencephalic opioid antinociception. Experiment 1 examined the effect of RVM excitatory amino acid (EAA) receptor antagonists on antinociception elicited by microinjection of morphine into the vlPAG. Mesencephalic morphine antinociception was eliminated by RVM administration of the competitive NMDA antagonist MK-801 on both the tail flick and jump tests, and was potently reduced by the non-competitive antagonist AP7. In contrast, RVM microinjection of the AMPA/kainate antagonist, CNQX failed to alter mesencephalic morphine antinociception on the tail-flick test, and produced only small, significant reductions in mesencephalic morphine antinociception on the jump test. Experiment 2 examined the effect of RVM cholinergic antagonists on antinociception elicited by microinjection of morphine into the vlPAG. The general muscarinic cholinergic antagonist, scopolamine, when microinjected into the RVM produced potent dose-dependent reductions in mesencephalic morphine antinociception on both the tail-flick and jump tests both in terms of the peak magnitude and the overall total duration of effects. The effects produced by M1 and M2 cholinergic receptor antagonists results were not as convincing, consistent, or specific as the scopolamine effects, where both M1 and M2 receptors are blocked. The nicotinic cholinergic antagonist, mecamylamine, microinjected into the RVM significantly and dose-dependently reduced mesencephalic morphine antinociception on the tail-flick and jump tests. Experiment 3 evaluated the ability of EAA (MK-801and AP7) cholinergic antagonists (scopolamine, mecamylamine) to alter mesencephalic beta-endorphin (BEND) antinociception. These data are clearly dissociated from morphine antinociception elicited from the vlPAG following RVM pretreatment since neither NMDA nor cholinergic receptor subtype antagonists reduced BEND antinociception from the vlPAG. An opioid mechanism of BEND was confirmed by reversal of BEND antinociception from the vlPAG by pretreatment with naltrexone. The findings in this study showed anatomical specificity, since injections of antagonists outside the RVM were ineffective in reducing mesencephalic opioid Antinociception. Pharmacological specificity was evidenced by dose-response relationships and effects of various receptor subtype antagonists. Further, the RVM antagonists alone did not significantly alter basal nociceptive thresholds, ruling out a cancellation effect. Although BEND and morphine create antinociception through the mu receptor, it is not entirely surprising that the antinociception produced was differentially sensitive to EAA and cholinergic antagonists, since several pharmacological contrasts have been made between these two systems. To explain these differences, the differential sensitivity of BEND to splice variants of the mu receptor is hypothesized.
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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.
