DOI
https://doi.org/10.25772/W7YC-0010
Author ORCID Identifier
https://orcid.org/0000-0003-3545-9594
Defense Date
2025
Document Type
Thesis
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Mohammed Imad Damaj
Abstract
Alcohol-induced peripheral neuropathy (AIPN) is a neurodegenerative disease caused by chronic alcohol intake and is associated with peripheral nerve damage and somatosensory symptoms, such as allodynia. Current treatments lack efficacy and do not target underlying pathology emphasizing the need for preclinical models of AIPN to elucidate mechanisms and novel targets. Thus, the purpose of the dissertation was to 1) characterize a mouse model of AIPN, 2) identify a novel target involved in AIPN and test a pharmacological target as a treatment strategy for AIPN, and 3) test the role of target in alcohol intake. In the first aim, we showed chronic alcohol intake induced hypersensitivity and deficits in spontaneous behaviors ethanol (EtOH) concentration-, time- and sex-dependent manners. Additionally, following long-term alcohol cessation, chronic alcohol-induced mechanical hypersensitivity persisted but cold hypersensitivity fully recovered. In our mouse model of AIPN chronic alcohol intake also produced spontaneous pain and deficits in spontaneous behaviors in time dependent manners. Duration of alcohol intake impacted alcohol-induced deficits in peripheral nerve electrophysiology amplitude and intra-epidermal nerve fiber density. We characterized an extensive time-course of chronic alcohol-induced neuroinflammation in the dorsal root ganglia (DRG) and spinal cord and found significant time, sex and tissue effects. We also investigated the role of acetaldehyde, the immediate metabolite of EtOH, in the development of AIPN and found aldehyde dehydrogenase-2 (ALDH2) inhibition accelerated and exacerbated the development of chronic alcohol-induced hypersensitivity in mice. In Aim 2, we showed chronic alcohol intake induces an upregulation of diacylglycerol lipase-β (DAGLβ) expression in the spinal cord. The development of chronic alcohol-induced mechanical and cold hypersensitivity was attenuated and prevented, respectively. Additionally, acute pharmacological inhibition of DAGLβ by KT109 produced antinociceptive effects and reversed chronic alcohol-induced mechanical and cold hypersensitivity. The antinociceptive effects of KT109 to reverse chronic alcohol-induced hypersensitivity did not undergo tolerance following repeated administration during alcohol intake or during alcohol withdrawal. Intrathecal administration demonstrated increased potency of the antinociceptive effects of KT109 in the reversal of chronic alcohol-induced hypersensitivity and elucidated a role for the spinal cord in mediating the antinociceptive effects of KT109 in a mouse model of AIPN. The third aim used a genetic and pharmacological approach to investigate a role of DAGLβ in alcohol intake, acute effects of alcohol and alcohol metabolism. Genetic knockout and pharmacological inhibition of DAGLβ decreased alcohol intake and preference in a continuous access two bottle choice alcohol model. Furthermore, pharmacological inhibition of DAGLβ decreased alcohol intake and preference in an intermittent access two bottle choice alcohol model. These effects were not mediated by any underlying effects of DAGLβ knockout or inhibition on the acute intoxicating effects of alcohol or EtOH metabolism. Overall, these results support that DAGLβ plays a role in the development of AIPN and implicated DAGLβ inhibition as a potential pharmacological strategy for the treatment of AIPN.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-7-2025