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dc.contributor.authorVanderah, Todd William.*
dc.creatorVanderah, Todd William.en_US
dc.date.accessioned2011-10-31T18:32:17Z
dc.date.available2011-10-31T18:32:17Z
dc.date.issued1995en_US
dc.identifier.urihttp://hdl.handle.net/10150/187190
dc.description.abstractOpioids are responsible for a number of effects but are employed primarily as analgesics. The discovery of endogenous opioids and multiple receptors have led to a better understanding of how analgesics function, and how both opioid receptors and endogenous ligands are regulated. The hypothesis of this dissertation states that levels of endogenous enkephalins are modulated by stress, inflammation and the endogenous peptide cholecystokinin (CCK) to alter the antinociceptive efficacy of μ and, possibly, δ opioids. Endogenous enkephalin release results in either direct antinociception or synergistically enhances the antinociceptive effects of the μ agonist morphine via δ receptors. This thesis will first detail how the administration of exogenous δ compounds can enhance the antinociceptive effects of a μ agonist. Exposure of mice to a cold-water swim-stress (CWSS) paradigm resulted in direct antinociception that was attenuated by opioid antagonists. Exposure to CWSS for a limited amount of time did not produce significant antinociception, but produced a marked enhancement of morphine antinociception. This enhancement was blocked by the administration of δ antagonists and (Leu⁵) enkephalin antisera. An antisense oligodeoxynucleotide was designed from the δ opioid receptor and administered to animals. Animals treated with the δ antisense and exposed to the CWSS paradigm showed a significant decrease in antinociception. Inflammation produced in the hind-paw of the mouse significantly enhanced the antinociceptive effects of morphine that was inhibited by δ antagonists and (Leu⁵) enkephalin antisera. The administration of a selective CCK(B) antagonist, L365,260 or CCK(B) antisense, enhances the antinociceptive potency of morphine. This enhancement is attenuated by δ antagonists, (Leu⁵) enkephalin antisera, as well as exhibits a two-way cross tolerance with δ agonists. L365,260 and an "enkephalinase" inhibitor, when coadministered, produced significant antinociception that was blocked by a δ antagonist and (Leu⁵) enkephalin antisera. Using polymerase chain reaction in search of a δ opioid receptor subtype, an orphan receptor was cloned and characterized as a member of the G protein-coupled receptor family. These data suggest that stress results in the release of (Leu⁵) enkephalin that enhances the antinociceptive effects of a μ-selective agonist morphine. Release of endogenous enkephalins may be regulated by the interactions of cholecystokinin at the CCK(B)receptor. Such information may lead to appropriate use of opiates in conjunction with CCK antagonists for the management of appropriate pain states.
dc.language.isoenen_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.titleThe direct and modulatory antinociceptive actions of endogenous and exogenous opioid delta agonists.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.contributor.chairPorreca, Franken_US
dc.contributor.chairYamamura, Henryen_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.contributor.committeememberRoeske, Williamen_US
dc.contributor.committeememberLaird, Hughen_US
dc.contributor.committeememberLai, Josephineen_US
dc.identifier.proquest9534695en_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.namePh.D.en_US
refterms.dateFOA2018-09-03T11:44:53Z
html.description.abstractOpioids are responsible for a number of effects but are employed primarily as analgesics. The discovery of endogenous opioids and multiple receptors have led to a better understanding of how analgesics function, and how both opioid receptors and endogenous ligands are regulated. The hypothesis of this dissertation states that levels of endogenous enkephalins are modulated by stress, inflammation and the endogenous peptide cholecystokinin (CCK) to alter the antinociceptive efficacy of μ and, possibly, δ opioids. Endogenous enkephalin release results in either direct antinociception or synergistically enhances the antinociceptive effects of the μ agonist morphine via δ receptors. This thesis will first detail how the administration of exogenous δ compounds can enhance the antinociceptive effects of a μ agonist. Exposure of mice to a cold-water swim-stress (CWSS) paradigm resulted in direct antinociception that was attenuated by opioid antagonists. Exposure to CWSS for a limited amount of time did not produce significant antinociception, but produced a marked enhancement of morphine antinociception. This enhancement was blocked by the administration of δ antagonists and (Leu⁵) enkephalin antisera. An antisense oligodeoxynucleotide was designed from the δ opioid receptor and administered to animals. Animals treated with the δ antisense and exposed to the CWSS paradigm showed a significant decrease in antinociception. Inflammation produced in the hind-paw of the mouse significantly enhanced the antinociceptive effects of morphine that was inhibited by δ antagonists and (Leu⁵) enkephalin antisera. The administration of a selective CCK(B) antagonist, L365,260 or CCK(B) antisense, enhances the antinociceptive potency of morphine. This enhancement is attenuated by δ antagonists, (Leu⁵) enkephalin antisera, as well as exhibits a two-way cross tolerance with δ agonists. L365,260 and an "enkephalinase" inhibitor, when coadministered, produced significant antinociception that was blocked by a δ antagonist and (Leu⁵) enkephalin antisera. Using polymerase chain reaction in search of a δ opioid receptor subtype, an orphan receptor was cloned and characterized as a member of the G protein-coupled receptor family. These data suggest that stress results in the release of (Leu⁵) enkephalin that enhances the antinociceptive effects of a μ-selective agonist morphine. Release of endogenous enkephalins may be regulated by the interactions of cholecystokinin at the CCK(B)receptor. Such information may lead to appropriate use of opiates in conjunction with CCK antagonists for the management of appropriate pain states.


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