Pharmacological and behavioral analysis of nociceptive modulation of rat prepro-orphanin FQ/nociceptin fragments in the amygdala of rats.
Item
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Title
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Pharmacological and behavioral analysis of nociceptive modulation of rat prepro-orphanin FQ/nociceptin fragments in the amygdala of rats.
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Identifier
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AAI3063883
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identifier
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3063883
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Creator
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Shane, Randi Michelle.
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Contributor
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Adviser: Richard J. Bodnar
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Date
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2002
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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 | Psychology, Psychobiology | Health Sciences, Pharmacology
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Abstract
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Orphanin FQ/nociceptin (OFQ/N) is a heptadecapeptide that binds with high affinity to the ORL-1/KOR-3 opioid receptor clone, yet binds poorly with traditional opioid receptors. OFQ/N previously exhibited a complex functional profile with relation to nociceptive processing, displaying pro-nociceptive properties in some studies, acting as an inhibitor of stress-induced analgesia in others, yet producing both spinal and supraspinal antinociceptive action in other studies. Prepro-Orphanin (ppORPH), the precursor gene for OFQ/N, contains several paired basic amino acids suggesting that it may be responsible for the production of additional biologically active peptide fragments. The first two studies of this dissertation examined the antinociceptive actions of rppOFQ/N135--151 and two of its truncated fragments, rppOFQ/N 135--145 and rppOFQ/N135--141, together with another biologically-active fragment of ppOrph, rppOFQ/N154--181, following microinjection into the amygdala. Since the amygdala has been implicated in both antinociceptive and stress-related responses, and possesses a dense distribution of ORL-1 receptors, it was hypothesized that OFQ/N would exhibit its antinociceptive and potential hyperalgesic effects in the amygdala. rppOFQ/N 135--151, its shorter-chained active fragments, rppOFQ/N135--145 and rpPOFQ/N135--141, as well as rppOFQ/N154--181 each produced antinociception as measured by reactivity to high-intensity radiant heat. In contrast to traditional mu and kappa opioids and beta-endorphin, none of the OFQ/N fragments in the amygdala exhibited antinociception on a test measuring shock reactivity. These ppOrph fragments failed to produce hyperalgesia as measured by reactivity to lower-intensity radiant heat. Therefore, OFQ/N fragments exert only antinociceptive responses in the amygdala with quantitative and qualitative differences relative to traditional opioid agonists. To establish whether OFQ/N-induced-antinociception is mediated by traditional opioids, the effects of systemic or intracerebral pretreatment with general or selective opioid receptor subtype antagonists was examined upon OFQ/N-induced antinociception elicited from the amygdala. This antinociceptive response was significantly reduced by general, mu, kappa, and delta opioid antagonists, indicating an intrinsic circuitry within the amygdala involving these receptors and the ORL-1 receptor. The final study evaluated regional interactions between the amygdala and ventrolateral periaqueductal gray (vlPAG) in mediating rppOFQ/N135--151-induced antinociception. OFQ/N-induced antinociception elicited from the amygdala was blocked by pretreatment with general and delta opioid antagonists in the vlPAG, whereas OFQ/N-induced antinociception elicited from the vlPAG was blocked primarily by pretreatment with general opioid antagonists in the amygdala. These studies indicate that OFQ/N appears to utilize a similar anatomical and functional pathway to that of the traditional opioid agonists in eliciting antinociceptive responses, and that its hyperalgesic properties are in all probability mediated by different supraspinal circuits.
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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.
