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01-08-2019 | Opioids

HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood–brain barrier integrity

Authors: Crystal R. Leibrand, Jason J. Paris, Austin M. Jones, Quamrun N. Masuda, Matthew S. Halquist, Woong-Ki Kim, Pamela E. Knapp, Angela D. M. Kashuba, Kurt F. Hauser, MaryPeace McRae

Published in: Journal of NeuroVirology | Issue 4/2019

Abstract

Poor antiretroviral penetration may contribute to human immunodeficiency virus (HIV) persistence within the brain and to neurocognitive deficits in opiate abusers. To investigate this problem, HIV-1 Tat protein and morphine effects on blood–brain barrier (BBB) permeability and drug brain penetration were explored using a conditional HIV-1 Tat transgenic mouse model. Tat and morphine effects on the leakage of fluorescently labeled dextrans (10-, 40-, and 70-kDa) into the brain were assessed. To evaluate effects on antiretroviral brain penetration, Tat+ and Tat− mice received three antiretroviral drugs (dolutegravir, abacavir, and lamivudine) with or without concurrent morphine exposure. Antiretroviral and morphine brain and plasma concentrations were determined by LC-MS/MS. Morphine exposure, and, to a lesser extent, Tat, significantly increased tracer leakage from the vasculature into the brain. Despite enhanced BBB breakdown evidenced by increased tracer leakiness, morphine exposure led to significantly lower abacavir concentrations within the striatum and significantly less dolutegravir within the hippocampus and striatum (normalized to plasma). P-glycoprotein, an efflux transporter for which these drugs are substrates, expression and function were significantly increased in the brains of morphine-exposed mice compared to mice not exposed to morphine. These findings were consistent with lower antiretroviral concentrations in brain tissues examined. Lamivudine concentrations were unaffected by Tat or morphine exposure. Collectively, our investigations indicate that Tat and morphine differentially alter BBB integrity. Morphine decreased brain concentrations of specific antiretroviral drugs, perhaps via increased expression of the drug efflux transporter, P-glycoprotein.

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Title: HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood–brain barrier integrity
Authors: Crystal R. Leibrand
Jason J. Paris
Austin M. Jones
Quamrun N. Masuda
Matthew S. Halquist
Woong-Ki Kim
Pamela E. Knapp
Angela D. M. Kashuba
Kurt F. Hauser
MaryPeace McRae
Publication date: 01-08-2019
Publisher: Springer International Publishing
Keywords: Opioids
Opioids
Lamivudine
Human Immunodeficiency Virus
Morphine
Dolutegravir
Lamivudine
Published in: Journal of NeuroVirology / Issue 4/2019
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-019-00757-8

At a glance: The STEP trials

Springer Medicine

HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood–brain barrier integrity

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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