Defense Date

2010

Document Type

Thesis

Degree Name

Master of Science

Department

Physiology

First Advisor

Carmen Sato-Bigbee

Abstract

While most cells of the central nervous system (CNS) express opioid receptors, the role of the endogenous opioid system in CNS development remains poorly understood. Identification of opioid functions during brain maturation is particularly crucial in light of the increasing trend in opioid abuse and the use of opioid drugs during pregnancy. New substitution therapies in pregnant opioid addicts include buprenorphine, a mu opioid receptor partial agonist and kappa opioid receptor antagonist. However, while clinical studies demonstrated buprenorphine efficacy in reducing neonatal withdrawal symptoms, there is a lack of information on the potential effects of this drug on brain development. Previous work from our laboratory has shown that perinatal exposure to buprenorphine induces dose-dependent alterations in rat brain myelination. These time-specific effects suggested that both therapeutic and supra- therapeutic doses of the drug could alter the normal pattern of oligodendrocyte development. In support of this hypothesis, this thesis work has now found that buprenorphine exerts direct actions on the oligodendrocytes that are highly dependent on both the drug dose and stage of cell differentiation. When exposed to buprenorphine, oligodendrocyte progenitors isolated from 3-day-old rat brain exhibit increased cell proliferation. In contrast, treatment of more mature oligodendrocytes obtained from 9-day-old rat brain induces dramatic dose- specific effects on cell process network extension and membrane outgrowth. These later effects are accompanied by significant parallel changes in the expression of the four major splicing isoforms of myelin basic protein (MBP), a critical component of the myelin membrane and mature myelinating oligodendrocytes. Furthermore, similar dose-specific effects on MBP expression are also elicited by methadone, a mu opioid receptor agonist already approved for the treatment of pregnant opioid addicts. Experiments with CTOP, a highly selective antagonist of the mu opioid receptor, further contribute to the idea that this receptor subtype plays an important function in controlling oligodendrocyte maturation. These findings underscore the potential effects of opioid exposure during brain maturation and further indicate an important regulatory role of the endogenous opioid system in the control of oligodendrocyte development and myelination.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

June 2010

Included in

Physiology Commons

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