Opioids 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.

Graduation date: 1996

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

Graduation date: 1995

Thesis (Ph. D.)--University of Michigan, 1997. / Includes bibliographical references.

Thesis (Ph.D.)--University of Michigan, 1997. / Includes bibliographical references.

published_or_final_version / abstract / Biochemistry / Master / Master of Philosophy

Includes bibliographical references (leaves 308-327) / xxviii, 356 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 2004?

We investigated the role of metabotropic glutamate receptors (mGluRs), and related intracellular second messengers, in the development of morphine tolerance and dependence. The mGluRs are divided into three groups: group I mGluRs are positively coupled to phosphatidylinositol (PI) hydrolysis, while group II and III mGluRs are negatively coupled to cyclic adensoine-3$ sp prime$,5$ sp prime$-monophosphate (cAMP) production. Opioid receptors are also coupled to these same systems, and have been shown to elicit changes in these messenger systems during chronic treatment. / We showed that chronic intracerebroventricular (i.c.v.) administration of selective group II and III mGluR antagonists concurrently with subcutaneous (s.c.) morphine significantly reduced the severity of precipitated withdrawal symptoms. Conversely, acute i.c.v. injection of a selective group II mGluR antagonist just prior to the precipitation of withdrawal significantly exacerbated the severity of abstinence symptoms. In addition, acute i.c.v. injection of a selective group II mGluR agonist just prior to the precipitation of withdrawal significantly reduced abstinence symptoms. From these results we hypothesized that chronic opioid treatment may induce a desensitization of group II mGluRs. / We also demonstrated that chronic i.c.v. infusion of a selective group I mGluR antagonist concurrently with s.c. morphine significantly attenuated the precipitated withdrawal syndrome. In addition, we showed that chronic i.c.v. antagonism of $ delta$-opioid receptors with a highly selective antagonist also decreased the development of morphine dependence, as well as tolerance. Since both group I mGluRs and $ delta$-opioid receptors are positively coupled to PI hydrolysis, further evidence for a role of products of PI hydrolysis in the development of morphine dependence was obtained when we showed that selective chronic inhibition of protein kinase C (PKC) activation, as well as selective chronic inhibition of intracellular Ca$ sp{2+}$ release, concurrently with morphine treatment significantly reduced the severity of abstinence symptoms. Thus, compensatory changes usually elicited by chronic opioid treatment may be counteracted by antagonizing receptors positively coupled to PI hydrolysis, as well as by inhibiting products of PI hydrolysis. / In the General Discussion, we propose a model based on the possible interaction of mGluRs and opioid receptors, via related intracellular second messengers, to explain the development of morphine dependence.