DOI

https://doi.org/10.25772/Z3ZK-YW33

Author ORCID Identifier

https://orcid.org/0000-0001-9441-4535

Defense Date

2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

MaryPeace McRae

Abstract

The complex mechanisms related to HIV infection, neurodegeneration, and chronic neuroinflammation collectively describe neuroHIV (Hauser et al. 2007; Chang et al. 2014; Smith et al. 2014). Specifically, opioid abuse, poor penetration of antiretroviral (ARV) drugs, chronic inflammation and neuronal injury/degeneration are all implicated in neuroHIV (Fantuzzi et al. 2003; Letendre et al. 2004; Verani et al. 2005; Duncan and Sattentau 2011; Hong and Banks 2015; Simoes and Justino 2015; Olivier et al. 2018; Murphy et al. 2019; Osborne et al. 2020). For the first time, we demonstrate that morphine, fentanyl, and methadone in vivo alter the brain accumulation of ARVs, impair the blood brain barrier (BBB), and dysregulate the immune response. The purpose of this body of work was to examine the interplay between HIV and opioids within the brain. Using two different animal model systems to mimic key aspects of the neuropathology of HIV, we examined three different opioids drugs and their effects on ARV accumulation in the striatum and hippocampus, transporters and tight junctions at the BBB, and chemokine concentrations. Morphine and fentanyl mediated BBB disruption through the modulation of tight junction and junction accessory proteins, claudin-5 and ZO-1, while methadone altered the expression of P-glycoprotein, an efflux transporter. All three opioids dysregulated chemokines in the presence of HIV-1 Tat and/or EcoHIV.

Rights

Kara Rademeyer © The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-11-2023

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