Patients with HIV often develop a painful neuropathy that is exacerbated by treatment with highly active anti-retroviral therapy (HAART). The recent development of animal models, created by application of gp120 to the sciatic nerve along with systemic administration of nucleoside reverse transcriptase inhibitors (NRTIs), have allowed studies of the pathogenesis of HIV/HAART neuropathic pain. We and others have described an increase in tumor necrosis factor (TNFa) in dorsal root ganglia (DRG) and activation of spinal microglia in the neuropathic pain. In other models of neuropathic pain, increases in reactive oxygen species (ROS) and decreases in GABAergic tone in the dorsal horn have been described. A disturbed balance between inhibitory and facilitatory impulses in the dorsal horn is the main mechanisms for pain hypersensitivity. The studies proposed will test the hypothesis that: pain in HIV/HAART neuropathy results from the production of proinflammatory cytokines that result in the release of ROS leading to a reduction in GABAergic tone in the dorsal horn of spinal cord. We propose a series of experiments with models of HIV/HAART neuropathy to: 1) define the changes of TNFa, ROS, glutamic acid decarboxylase (GAD) and GABA in DRG and spinal cord in HIV-associated pain;2) critically test the relationship between elevations in TNFa and ROS;3) examine the relationship between ROS and GABAergic tone;and 4) determine whether HIV-associated pain can be reduced by herpes simplex virus vector-mediated gene transfer to increase anti-inflammatory cytokine and inhibitory amino acid to DRG and their neurochemical mechanisms. The results of these studies will provide important insights into the pathogenesis of neuropathic pain in patients with HIV/AIDS, and may provide preclinical evidence for a novel therapy.

Public Health Relevance

One of the most debilitating neurological complications of HIV infection is painful neuropathy associated with nucleoside reverse transcriptase inhibitors (NRTIs). This study may help us understand the mechanism of pain better so that we can find a novel way to reduce pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066792-04
Application #
8259176
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$326,841
Indirect Cost
$105,220
Name
University of Miami School of Medicine
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Kanda, H; Kanao, M; Liu, S et al. (2016) HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a. Gene Ther 23:340-8
Kanda, Hirotsugu; Liu, Shue; Iida, Takafumi et al. (2016) Inhibition of Mitochondrial Fission Protein Reduced Mechanical Allodynia and Suppressed Spinal Mitochondrial Superoxide Induced by Perineural Human Immunodeficiency Virus gp120 in Rats. Anesth Analg 122:264-72
Guedon, Jean-Marc G; Wu, Shaogen; Zheng, Xuexing et al. (2015) Current gene therapy using viral vectors for chronic pain. Mol Pain 11:27
Kanao, Megumi; Kanda, Hirotsugu; Huang, Wan et al. (2015) Gene Transfer of Glutamic Acid Decarboxylase 67 by Herpes Simplex Virus Vectors Suppresses Neuropathic Pain Induced by Human Immunodeficiency Virus gp120 Combined with ddC in Rats. Anesth Analg 120:1394-404
Zheng, Wenwen; Huang, Wan; Liu, Shue et al. (2014) IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats. Mol Pain 10:49
Huang, W; Zheng, W; Liu, S et al. (2014) HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity. Gene Ther 21:328-36
Huang, Wan; Zheng, Wenwen; Ouyang, Handong et al. (2014) Mechanical allodynia induced by nucleoside reverse transcriptase inhibitor is suppressed by p55TNFSR mediated by herpes simplex virus vector through the SDF1α/CXCR4 system in rats. Anesth Analg 118:671-80
Zheng, Wenwen; Huang, Wan; Liu, Shue et al. (2014) Interleukin 10 mediated by herpes simplex virus vectors suppresses neuropathic pain induced by human immunodeficiency virus gp120 in rats. Anesth Analg 119:693-701
Zheng, Xuexing; Zheng, Wenwen; Liu, Shue et al. (2012) Crosstalk between JNK and NF-κB in the KDO2-mediated production of TNFα in HAPI cells. Cell Mol Neurobiol 32:1375-83
Sun, J; Liu, S; Mata, M et al. (2012) Transgene-mediated expression of tumor necrosis factor soluble receptor attenuates morphine tolerance in rats. Gene Ther 19:101-8

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