Endopeptidase-24.15 and opioid antinociception: Characterization and specificity of action.
Item
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Title
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Endopeptidase-24.15 and opioid antinociception: Characterization and specificity of action.
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Identifier
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AAI9130335
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identifier
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9130335
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Creator
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Kest, Benjamin.
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Contributor
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Adviser: R. J. Bodnar
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Date
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1991
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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
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Abstract
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It is commonly accepted that extracellular proteolysis is the primary method of CNS opioid peptide inactivation. Much in vivo and in vitro evidence implicates aminopeptidase, ACE, and endopeptidase-24.11 as the primary participants. In vitro and in vivo studies with endopeptidase-24.15 demonstrate that it too possesses high affinity for several opioids, and that degradation could be halted by specific active-site directed inhibitors. Conclusive demonstration of the involvement of endopeptidase-24.15 in the metabolism of the opioids however requires the demonstration that its inhibition in vivo leads to changes in those functions which are dependent upon opioid peptide function. Thus, the aim of this dissertation was to assess the effects of endopeptidase-24.15 upon opioid-mediated pain inhibitory processes through the use of selective inhibitors. Three different but integrated lines of inquiry were pursued. First, the endopeptidase-24.15 inhibitors cFP-A(D)AF-pAB and cFP-AAF-pAB were compared to the endopeptidase-24.11 inhibitor cFP-F-pAB for alterations upon basal nociceptive thresholds. Second, inhibitor effects upon opioid peptide antinociception were assessed by comparing the ability of cFP-AAF-pAB and cFP-F-pAB to increase MERGL and met-enkephalin antinociception, and induce dynorphin A{dollar}\sb{lcub}1-8{rcub}{dollar} antinociception. Finally, the role of endopeptidase-24.15 in the phasically-activated, opioid-mediated pain inhibitory system was evaluated through inhibitor pretreatment prior to a cold-water swim stressor. Inhibitors of endopeptidase-24.15 produced time- and dose-dependent effects comparable to cFP-F-pAB upon basal nociceptive thresholds. While cFP-AAF-pAB co-administration was more effective in potentiating dynorphin A{dollar}\sb{lcub}1-8{rcub}{dollar}, MERGL, and opioid-mediated cold-water swim antinociception, cFP-F-pAB was more effective upon met-enkephalin antinociception. The general opioid receptor antagonists naloxone and naltrexone blocked basal threshold increases and dynorphin A{dollar}\sb{lcub}1-8{rcub}{dollar} and cold-water swim antinociception. Central pretreatment with the kappa antagonist nor-BNI, but not the mu antagonist {dollar}\beta{dollar}-FNA, blocked cFP-AAF-pAB-dynorphin A{dollar}\sb{lcub}1-8{rcub}{dollar} antinociception. Central cFP-AAF-pAB, alone or after co-administration with dynorphin A{dollar}\sb{lcub}1-8{rcub}{dollar}, did not produce motor impairment, suggesting changes in pain perception. The data suggest that endopeptidase-24.15 plays a modulatory role upon opioid-mediated antinociceptive processes, and that inhibitors of endopeptidase-24.15 may serve as useful scientific probes and clinical analgesics.
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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.
