Antisense mapping of opioid receptor clones: Role in ingestive behavior in rats.
Item
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Title
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Antisense mapping of opioid receptor clones: Role in ingestive behavior in rats.
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Identifier
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AAI9908340
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identifier
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9908340
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Creator
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Leventhal, Liza.
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Contributor
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Adviser: Richard J. Bodnar
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Date
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1998
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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, Psychobiology | Biology, Neuroscience | Psychology, Physiological
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Abstract
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The endogenous opioid system is one of a number of neurotransmitter and peptide systems that modulate ingestive behavior. Previous studies investigating opioid modulation of ingestive behavior employed selective agonists and antagonists which are cross reactive and lack relative specificity. The cloning of the opioid receptors made it possible to employ molecular knockdown techniques, including antisense oligodeoxynucleotides (AS ODNs) to investigate opioid receptor clones in behaving animals. AS ODN probes directed against each of the four exons of the MOR-1 clone were found to significantly reduce spontaneous food intake and body weight, whereas a missense control failed to exert effects. Thus, the MOR-1 clone encodes the receptor modulating spontaneous weight and intake. Subsequently, AS ODN probes directed against either exons 1 or 4, but not exons 2 or 3, of the MOR-1 clone were found to block hyperphagia, operationally defined as an increase in spontaneous food intake, induced by the {dollar}\mu{dollar} agonists, DAMGO and morphine. In contrast, AS ODN probes directed against either exons 2 or 3, but not 1 or 4 of the MOR-1 clone blocked hyperphagia induced by the potent morphine metabolite, M6G. Pharmacological studies with selective opioid antagonists confirmed the {dollar}\mu{dollar} receptor mediation of hyperphagia induced by DAMGO and M6G. M6G-induced hyperphagia was also unaffected by AS ODN probes directed against the DOR-1, KOR-1 and KOR-3/ORL-1 clones which were each capable of blocking intake induced by their respective agonists. Thus, the AS ODN profile for hyperphagia induced by DAMGO, morphine and M6G was identical to that observed in analgesic assays, and argues for the existence of multiple splice variants of the MOR-1 gene. Finally, AS ODNs directed against each of the three exons of the KOR-3/ORL-1 clone blocked hyperphagia intake induced by the recently-identified opioid peptide, OFQ/N, indicating that the KOR-3/ORL-1 clone encodes the receptor mediating OFQ/N-induced food intake. These data provide critical molecular evidence for the opioid mediation of ingestion, an important homeostatic behavior, indicating that the AS ODN technique should be employed as a useful tool to investigate the molecular substrates mediating other motivated behaviors, including those involved with addiction.
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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.
