Persistent sensory changes and sex differences in transgenic mice conditionally expressing HIV-1 Tat regulatory protein.

Autor: Toma W; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA., Paris JJ; Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, USA; Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, USA., Warncke UO; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA., Nass SR; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA., Caillaud M; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA., McKiver B; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA., Ondo O; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA., Bagdas D; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA., Bigbee J; Department of Anatomy and Neurobiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA., Knapp PE; Department of Anatomy and Neurobiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA; Institute for Drug and Alcohol Studies, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA., Hauser KF; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Anatomy and Neurobiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA; Institute for Drug and Alcohol Studies, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA., Damaj MI; Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: m.damaj@vcuhealth.org.
Jazyk: angličtina
Zdroj: Experimental neurology [Exp Neurol] 2022 Dec; Vol. 358, pp. 114226. Date of Electronic Publication: 2022 Sep 10.
DOI: 10.1016/j.expneurol.2022.114226
Abstrakt: HIV-associated sensory neuropathies (HIV-SN) are prevalent in >50% of patients aged over 45 years many of which report moderate to severe chronic pain. Previous preclinical studies have investigated the mechanisms by which HIV-1 causes sensory neuropathies and pain-like behaviors. The aim of the present study is to delineate the role of chronic HIV-1 trans-activator of transcription protein (Tat) exposure in the development of neuropathy in mice. The temporal effects of conditional Tat expression on the development of hypersensitivity to mechanical (von Frey filaments) and thermal (heat or cold) stimuli were tested in male and female mice that transgenically expressed HIV-1 Tat in a doxycycline-inducible manner. Inducing Tat expression produced an allodynic response to mechanical or cold (but not heat) stimuli that respectively persisted for at least 23-weeks (mechanical hypersensitivity) or at least 8-weeks (cold hypersensitivity). Both allodynic states were greater in magnitude among females, compared to males, and mechanical increased hypersensitivity progressively in females over time. Acute morphine or gabapentin treatment partly attenuated allodynia in males, but not females. Irrespective of sex, Tat reduced intraepidermal nerve fiber density, the mean amplitude of sensory nerve action potentials (but not conductance), engagement in some pain-related ethological behaviors (cage-hanging and rearing), and down-regulated PPAR-α gene expression in lumbar spinal cord while upregulating TNF-α expression in dorsal root ganglion. Taken together, these data reveal fundamental sex differences in mechanical and cold hypersensitivity in response to Tat and demonstrate the intractable nature in female mice to current therapeutics. Understanding the role of Tat in these pathologies may aid the design of future therapies aimed at mitigating the peripheral sensory neuropathies that accompany neuroHIV.
Competing Interests: Declaration of Competing Interest None.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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