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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.

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Thesis (Ph. D.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains vi, 71 p. : ill. Includes abstract. Includes bibliographical references (p. 64-71).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1956. / Typescript. Vita. Includes: The formation of vicinal dichlorides in the reaction of alcohols with phosphorus pentachloride / By Harlan L. Goering and Fred H. McCarron. Reprinted from Journal of the American Chemical Society, vol. 78, no. 10 (20 May 1956), p. 2270-2274. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M.S.)--University of Wisconsin--Madison, 1940. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 24-27).

La morphine constitue l'un des analgésiques les plus utilisés en milieu hospitalier pour soulager les douleurs aiguës et chroniques. Elle exerce ses effets analgésiques en se liant aux récepteurs opioïdes μ (MOR) présents au niveau central et périphérique et possède des effets secondaires, incluant la tolérance, qui limitent son usage à long terme. La première partie de mes travaux avait pour objectif d'étudier le phénomène de tolérance à la morphine et d'en déterminer les mécanismes sous-jacents. A l'heure actuelle, ce phénomène est décrit comme résultant d'une désensibilisation des MOR conduisant à leur endocytose. Nos résultats montrent qu'en cas de tolérance, le catabolisme de la morphine est exacerbé au niveau du système nerveux central. Mes travaux ont également porté sur la caractérisation de la Créatine Kinase (CK) comme étant une protéine liant la morphine à très haute affinité. Nos résultats montrent que la CK possède 2 sites de liaison pour la morphine avec des affinités similaires. En étudiant l'effet potentiel de la CK sur l'analgésie induite par la morphine in vivo, nous avons mis en évidence, que les peptides correspondant aux 2 sites de liaison à la morphine étaient par eux-mêmes analgésiques et que cette analgésie semblait dépendre des récepteurs opioïdes. / Morphine is one of the most used analgesics in hospitals to relieve acute and chronic pain. Morphine exerts its analgesic effects by binding central and peripheral μ opioid receptors (MORs) and has many side effects that limit its long-term use including tolerance. The first part of my thesis was aimed to study the phenomenon of morphine tolerance and to determine the underlying mechanisms. Previously, this phenomenon was explained as resulting !rom MORs desensitization by endocytosis. However, our results show that in case of tolerance, the catabolism of morphine is exacerbated in the central nervous system in particular in astocytes. The second part of my work has focused on the characterization of the Creatine Kinase (CK) as a novel protein that binds morphine with a high affinity. Our results showed that CK has two binding sites with a similar affinity for morphine. Surprisingly, by studying the potential effect of CK on morphine-induced analgesia in vivo, we noticed that the two peptides corresponding to morphine binding sites are analgesics and such analgesia seems to be mediated by opioid receptors.

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