published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

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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published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

published_or_final_version / Biochemistry / Master / Master of Science

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Biochemistry / Master / Master of Philosophy

published_or_final_version / Pharmacology / Master / Master of Philosophy

The present study used the conditioned place preference (CPP) paradigm to examine the neural mechanisms underlying morphine's rewarding effect in the rat. Of thirteen sites tested with intra-cerebral morphine injections, only the ventral tegmental area (VTA) and periaqueductal gray (PAG) produced a CPP, suggesting that morphine's rewarding effect is initiated by an action at these sites. The CPPs induced by intra-VTA and intra-PAG morphine may be produced by different mechanisms because animals conditioned with these two injections exhibited different patterns of behaviour during testing. Injections of a quaternary opioid antagonist into either the VTA or PAG blocked a CPP to systemic morphine, confirming that opiate-induced reward is mediated via opioid receptors in these sites. Lesions of the pedunculopontine tegmental nucleus (PPT$ rm sb{g}),$ ventral striatum (VS), PAG, or fornix reduced a CPP to morphine, although PAG and fornix lesioned animals displayed a CPP when tested in a drugged state. These findings suggest that PPT$ rm sb{g}$ and VS lesions reduce the rewarding effect of morphine, and that PAG and fornix lesions disrupt the ability to retrieve information about the relationship between conditioned and unconditioned stimuli.