DOI
https://doi.org/10.25772/F4K8-G735
Defense Date
2019
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Hamid I. Akbarali
Second Advisor
William L. Dewey
Third Advisor
Aron H. Lichtman
Fourth Advisor
Ian S. Ramsey
Fifth Advisor
John R. Grider
Abstract
Opioids such as morphine are frequently used in the clinic to treat pain. However, the perennial bane of chronic opioid use is the rapid development of tolerance to the analgesic effects but delayed development of tolerance to the respiratory depressant and constipating effects. As constipation is one of the most common opioid-related adverse effects in humans, it is important to delineate mechanisms that drive opioid tolerance in the ileum and lack of it in the colon. The overarching goal of this thesis was to investigate mechanisms of morphine tolerance in the ileum by comparing the mechanism of morphine tolerance in ileum myenteric plexus neurons and dorsal root ganglia (DRG) neurons. Myenteric plexus neurons are integral to the motor function of the ileum, whereas DRG neurons are important components of peripheral nociceptive sensation. We also examined the mechanism of morphine tolerance development to small intestinal transit and to antinociception at the systemic level in male and female mice. Studies presented in this dissertation demonstrate that the mechanism of morphine tolerance in the mouse ileum is not contingent on b-arrestin 2. In fact, tolerance in the small intestine might be mediated by a b-arrestin 2-independent mechanism following protein kinase C-induced phosphorylation of the m-opioid receptor. We also demonstrate that morphine tolerance to antinociception is not solely dependent on b-arrestin 2, and is mediated by b-arrestin 2-dependent and-independent mechanisms. Lastly, we have shown how sex of the animal can influence mechanisms underlying the development of morphine tolerance. Collectively, the findings presented here increase our understanding of the mechanisms by which morphine tolerance develops in the ileum and to antinociception.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-6-2019
Included in
Behavioral Neurobiology Commons, Cellular and Molecular Physiology Commons, Laboratory and Basic Science Research Commons, Molecular and Cellular Neuroscience Commons, Molecular Biology Commons, Pharmacology, Toxicology and Environmental Health Commons