Defense Date

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biochemistry

First Advisor

CARMEN SATO-BIGBEE

Abstract

Myelin is an extensive cell membrane produced by oligodendrocytes to ensheath neuronal axons in the central nervous system with the primary goal of maximizing the efficiency of electrochemical impulse transmission. During brain development, oligodendrocytes differentiate into myelin forming cells in a tightly regulated process which makes them vulnerable to multiple insults. Previous results from the laboratory showed that the timing of oligodendrocyte differentiation and rat brain myelination were altered by perinatal exposure to buprenorphine and methadone, opioid analogues used for treating pregnant addicts. The mechanism by which these opioids exerted their effects involved two opioid receptors, the μ-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOR). However, the role of these receptors and their endogenous ligands in controlling the timing of myelination under normal physiological conditions of brain development is not known. In this dissertation, we found that the endogenous MOR ligand endomorphin-1 (EM-1) acts as a strong promoter of rat pre-oligodendrocyte differentiation, but surprisingly, this effect is observed only in cells isolated from female pups. Interestingly, the stimulatory action of EM-1 was abolished upon co-incubation with the endogenous NOR ligand, nociceptin. Moreover, injections of NOR antagonist to 9-day-old female and male rat pups accelerated rat brain myelination in female rat pups with no significant changes in their male counterparts. Interestingly, the lack of major sex-dependent differences in developmental brain levels of EM-1 and nociceptin and the presence of the two receptors MOR and NOR in male and female oligodendrocytes suggested that the observed sex-specific responses may be highly dependent on critical intrinsic sex-dependent differences within these cells. Although nociceptin alone did not exert observable effects on pre-oligodendrocyte maturation, it increased the number of cells expressing Ki-67, a cell proliferation indicator, in oligodendrocyte progenitor cultures. These results suggest that nociceptin may be playing a stage specific role in oligodendrocyte development during brain maturation. The finding of critical functions of EM-1 and nociceptin in the developing female oligodendrocytes and brain myelination highlights the need for considering sexual dimorphism in the design of safer and more effective therapeutic approaches for treating opioid abuse, pain, and demyelinating disease as multiple sclerosis.

Rights

© Esraa M. Mohamed

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

6-28-2019

Available for download on Saturday, July 13, 2024

Share

COinS