AuthorHeyman, Julius Scott.
KeywordsOpioids -- Receptors.
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PublisherThe University of Arizona.
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.
AbstractOpioids produce myriad effects, perhaps the most clinically relevant of which is the relief of pain. The understanding of the functions mediated by opioid systems is complicated greatly by the presence of several opioid receptor types. Understanding the functions associated with specific opioid receptors may lead to the development of receptor selective drugs which elicit only desirable effects. This dissertation addresses the possibility that supraspinal and spinal opioid δ receptors mediate and/or modulate thermal antinociceptive processes in the mouse. A number of approaches were utilized in parallel in this investigation which included: (1) the determination of the naloxone pA₂ in vivo against the opioid agonists morphine (μ), (D-Ala², NMePhe⁴, Gly-ol]enkephalin (DAMGO)(μ) and [D-Pen², D-Pen⁵]enkephalin (DPDPE)(δ); (2) the investigation of possible cross-tolerance between morphine and DPDPE; and (3) antagonism studies using N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-Oh, (ICI 174,864)(δ), β-funaltrexamine(β-FNA)(μ) and naloxonazine (μ₁). No differences were found in the apparent pA₂ values for naloxone against morphine, DAMGO and DPDPE at either supraspinal or spinal sites, but was demonstrated in the spinal cord. The antinociceptive effects of i.c.v. morphine and DAMGO were antagonized by β-FNA and naloxonazine, but not ICI 174,864. I.c.v. DPDPE antinociception was blocked by ICI 174,864, but not β-FNA or naloxonazine. Neither ICI 174,864 nor naloxonazine blocked the antinociceptive effects of i.th. morphine or DAMGO. ICI 174,864, but not naloxonazine, antagonized i.th. DPDPE antinociception. I.th. morphine, but not i.th. DPDPE antinociception was blocked by β-FNA. Co-administration of sub-effective doses of DPDPE and DAMA were shown to potentiate and attenuate, respectively, i.c.v., morphine antinociception. This potentiation was evident in naive and morphine tolerant mice, and was blocked by ICI 174,864. The modulatory effects of DPDPE and DAMA were blocked by β-FNA, but not naloxonazine. In contrast the supraspinal sites, i.th. DPDPE had no effect upon i.th. morphine antinociception. Collectively, the data demonstrate that supraspinal and spinal opioid δ receptors can directly mediate antinociception in the mouse. Additionally, supraspinal, but not spinal, δ receptors are also capable of indirectly modulating antinociceptive.
Degree ProgramPharmacology and Toxicology