Millions of HIV-1/AIDS patients suffer chronic pain. Morphine is a common analgesic for pain relief in these patients. Ironically, clinical data indicat that repeated morphine treatment leads a heightened chronic pain state. This problem is of great clinical importance since it suggests that HIV-1 patients receiving morphine to relieve pain may actually develop more pain as a result of treatment. Thus, there is a compelling need to understand how chronic morphine use causes this condition in HIV-1 patients. Using a mouse model that develops extensive abnormalities similar to the pain-related pathologies in HIV-1 human patients, we observed that chronic morphine administration potentiates HIV-1 gp120 (i.t.)-induced pain. Concomitantly, we found that chronic use of morphine also dramatically enhances gp120 (i.t.)-induced astrocyte activation in the spinal cord dorsal horn (SDH), the first pain processing center in the CNS. Our recent work suggests a key role of astrocyte activation in pain pathogenesis in HIV-1 patients. Hence, the morphine-enhanced astrocyte activation may provide an important cellular basis for morphine to potentiate HIV-related pain. The goal of this project is to understand the mechanism and consequences of the gp120-morphine interplay in astrocyte activation in the SDH. Our preliminary data show that chronic administration of gp120 and morphine cooperatively up-regulate Wnt5a, a secreted signaling protein that activates astrocytes but not microglia in the SDH. Based on ample preliminary data, we hypothesize that gp120 and morphine synergistically activate astrocytes by stimulating Wnt5a signaling and that the activated astrocytes enhance gp120-induced hyperalgesia by promoting cytokine signaling. This hypothesis will be tested in the proposed project under three specific aims.
In Aim 1, we will identify the molecular pathways through which the gp120-morphine interaction stimulates astrocyte activation in the SDH.
In Aim 2, we will establish the role of the mitochondria-inflammasome axis in control of cytokine signaling in astrocytes activated by gp120 and morphine. Finally in Aim 3, we will determine the contribution of astrocyte activation to the morphine potentiation of gp120-induced hyperalgesia. Results from this study will significantly improve our understanding of the mechanism by which the interplay of gp120 and morphine activates astrocytes in the SDH. The results will also help us understand how chronic morphine use enhances HIV-associated pain. The research has significant potential for the development of novel approaches to prevent the morphine-potentiation of hyperalgesia in HIV-1 patients.

Public Health Relevance

Morphine is a common prescription drug for pain relief in HIV-1 patients, but its chronic use may lead to an enhanced pain state. This project will help us better understand how the interaction of HIV-1 infection and chronic morphine use may cause the problem so that we can design therapies to block the development of the side effect.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA036165-02
Application #
8719076
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Sorensen, Roger
Project Start
2013-08-15
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Galveston
State
TX
Country
United States
Zip Code
77555
Wang, Yongdi; Liao, Jinxu; Tang, Shao-Jun et al. (2017) HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/?-Catenin Signaling Pathway. J Mol Neurosci 62:199-208
Tang, Shao-Jun (2017) Potential Role of Phase Separation of Repetitive DNA in Chromosomal Organization. Genes (Basel) 8:
Wu, Ting; Zhang, Juan; Geng, Mingxing et al. (2017) Nucleoside reverse transcriptase inhibitors (NRTIs) induce proinflammatory cytokines in the CNS via Wnt5a signaling. Sci Rep 7:4117
Obermeit, Lisa C; Beltran, Jessica; Casaletto, Kaitlin B et al. (2017) Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining ""symptomatic"" versus ""asymptomatic"" HAND. J Neurovirol 23:67-78
Tang, Shao-Jun (2017) New Evidence for the Theory of Chromosome Organization by Repetitive Elements (CORE). Genes (Basel) 8:
Ru, Wenjuan; Tang, Shao-Jun (2017) HIV-associated synaptic degeneration. Mol Brain 10:40
Shi, Yuqiang; Shu, Jianghong; Liang, Zongsuo et al. (2016) EXPRESS: Oligodendrocytes in HIV-associated pain pathogenesis. Mol Pain 12:
Ru, Wenjuan; Tang, Shao-Jun (2016) HIV-1 gp120Bal down-Regulates Phosphorylated NMDA Receptor Subunit 1 in Cortical Neurons via Activation of Glutamate and Chemokine Receptors. J Neuroimmune Pharmacol 11:182-91
Li, Xiang-Yao; Wan, You; Tang, Shao-Jun et al. (2016) Maladaptive Plasticity and Neuropathic Pain. Neural Plast 2016:4842159
Tang, Shao-Jun (2016) The R-Operon: A Model of Repetitive DNA-Organized Transcriptional Compartmentation of Eukaryotic Chromosomes for Coordinated Gene Expression. Genes (Basel) 7:

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