DOI
https://doi.org/10.25772/1K7M-QB91
Author ORCID Identifier
0000-0002-3524-0958
Defense Date
2024
Document Type
Thesis
Degree Name
Master of Science
Department
Pharmacology & Toxicology
First Advisor
Dr. M. Imad Damaj
Abstract
Millions of Americans abuse opioids every year, and roughly 7 million Americans are currently suffering from opioid use disorder (OUD) in the United States. A major component of treating OUD is to manage physical and non-physical withdrawal symptoms that arise from the discontinuation of opioid use or from tapering off opioids for patients with chronic pain. Current treatment strategies have been shown to have side effects or only assuage some withdrawal symptoms. This can cause individuals to relapse to alleviate their discomfort so therefore newer, and safer treatment options should be developed to relieve opioid withdrawal-related symptoms. Most rodent withdrawal studies involve precipitating somatic withdrawal signs with naloxone or naltrexone, but spontaneous withdrawal paradigms are rarely assessed. Recent studies in rodents suggest that blockade of nicotinic acetylcholine receptors, specifically the α3β4* subtype could be a potential target for opioid withdrawal. In this thesis, we developed and validated a spontaneous oxycodone withdrawal model in mice using subcutaneous infusions of oxycodone over 7 days. The model revealed that oxycodone-dependent mice displayed mechanical hypersensitivity and was reversed 45 days after minipump removal. Utilizing this model, we hypothesized that two α3β4* nAChR-targeting compounds, partial agonist AT-1001 and antagonist SR16584, will reduce oxycodone-induced withdrawal signs in mice. Our results show that AT-1001 reduced somatic signs in mice without impacting the antinociceptive effects of oxycodone. SR16584 also reduced somatic signs in oxycodone- treated mice. Based on our results, we are suggesting that α3β4* nicotinic receptors should be considered as a pharmacological target for opioid withdrawal management.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-9-2024