Glial TNFα in the Spinal Cord Regulates Neuropathic Pain Induced by HIV gp120 Application in Rats

Zheng, Wenwen; Ouyang, Handong; Zheng, Xiaodong; Li, Shue; Mata, Marina; Fink, David J.; Hao, Shuanglin

doi:10.1186/1744-8069-7-40

Cited by 89 publications

(87 citation statements)

References 61 publications

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“…HIV-gp120 also has direct and indirect effects on nerves by stimulating the nervous system to release pro-inflammatory cytokines [1,22,31,32]. Pro-inflammatory cytokines can activate SGCs, as a feedback, SGC activation may cause more release of pro-inflammatory cytokines, that will increase abnormal neuronal excitability and contribute to neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2′,3′-dideoxycytidine

Xie

Zhou

et al. 2017

Purinergic Signalling

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The direct neurotoxicity of HIV and neurotoxicity of combination antiretroviral therapy medications both contribute to the development of neuropathic pain. Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in mechanical and thermal hyperalgesia. The P2Y 12 receptor expressed in SGCs of the DRG is involved in pain transmission. In this study, we explored the role of the P2Y 12 receptor in neuropathic pain induced by HIV envelope glycoprotein 120 (gp120) combined with ddC (2′,3′-dideoxycytidine). A rat model of gp120+ddC-induced neuropathic pain was used. Peripheral nerve exposure to HIVgp120+ddC increased mechanical and thermal hyperalgesia in gp120+ddC-treated model rats. The gp120+ddC treatment increased expression of P2Y 12 receptor mRNA and protein in DRG SGCs. In primary cultured DRG SGCs treated with gp120+ddC, the levels of [Ca 2+ ] i activated by the P2Y 12 receptor agonist 2-(Methylthio) adenosine 5′-diphosphate trisodium salt (2-MeSADP) were significantly increased. P2Y 12 receptor shRNA treatment inhibited 2-MeSADPinduced [Ca 2+ ] i in primary cultured DRG SGCs treated with gp120+ddC. Intrathecal treatment with a shRNA against P2Y 12 receptor in DRG SGCs reduced the release of proinflammatory cytokines, decreased phosphorylation of p38 MAPK in the DRG of gp120+ddC-treated rats. Thus, downregulating the P2Y 12 receptor relieved mechanical and thermal hyperalgesia in gp120+ddC-treated rats.

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Section: Discussionmentioning

confidence: 99%

P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2′,3′-dideoxycytidine

Xie

Zhou

et al. 2017

Purinergic Signalling

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“…21 In this study, we tested if neuropathic pain induced by HIV gp120 affected TNFa, CXCR4 and SDF1a expression in the DRG and the spinal dorsal horn. To induce HIV neuropathic pain, rats received a recombinant gp120 application to the sciatic nerve 10,15 (for details, see Materials and methods section). In the sham group, rats received an identical surgery except gp120.…”

Section: Resultsmentioning

confidence: 99%

“…[16][17][18][19][20] Along with others, we have reported that the application of the recombinant gp120 to the sciatic nerve increases TNFa expression in the DRG and the spinal cord. 10,15 It is possible that CXCR4 acts as an important inflammatory factor in the neuropathogenesis of HIV/AIDS. 21,22 CXCR4 is required for gp120-induced cell death in human neuroblastoma cells.…”

Section: And Hao 7 )mentioning

confidence: 99%

“…10,12 This pain behavior is associated with inflammatory activation in the DRG and the spinal cord. 10,13,15 Proinflammatory cytokines (for example, tumor necrosis factor-a (TNFa)) have an important role in the development and maintenance of inflammatory and neuropathic pain in preclinical studies. [16][17][18][19][20] Along with others, we have reported that the application of the recombinant gp120 to the sciatic nerve increases TNFa expression in the DRG and the spinal cord.…”

Section: And Hao 7 )mentioning

confidence: 99%

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HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity

et al. 2014

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Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite extensive research, the detailed neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. In this study, we investigated the role of proinflammatory molecules, tumor necrosis factor-α (TNFα), CXCR4 and stromal-derived factor-1 α (SDF1α), in the L4/5 dorsal root ganglia (DRG) and the spinal dorsal horn in HIV gp120 protein-mediated neuropathic pain. Our results showed that the application of HIV gp120 to the sciatic nerve induced upregulation of TNFα, CXCR4 and SDF1α in both the DRG and the lumbar spinal dorsal horn. Non-replicating herpes simplex virus (HSV) vector encoding the p55TNFSR gene and producing a TNF-soluble receptor (TNFSR) to block bioactivity of TNFα reversed mechanical allodynia. Intrathecal AMD3100 (CXCR4 antagonist) increased mechanical threshold. The HSV vectors expressing p55TNFSR reversed upregulation of TNFα, CXCR4 and SDF1α induced by gp120 in the DRG and the spinal dorsal horn. These studies suggest that proinflammatory TNFα to the CXCR4/SDF1 pathway has an important role in the HIV-related neuropathic pain state and that blocking the proinflammatory cytokines or chemokines is able to reduce neuropathic pain. This work provides a novel gene therapy proof-of-concept for HIV-associated neuropathic pain.

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“…Injured neurons secrete the chemokine MCP-1, thereby attracting and activating astrocytes [86]. Astrocytes that migrated to, and were activated at, the dorsal root ganglions release IL-1 and TNF, which have been implicated in the pathogenesis of neuropathic pain [87,88].…”

Section: Glial Migration To Sites Of Injury and Regenerationmentioning

confidence: 99%

Integrins and Nitric Oxide in the Regulation of Glial Cells: Potential Roles in Pathological Pain

Okamoto¹,

Shimaoka²

2013

J Anesthe Clinic Res

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Glial cells form physical connections with neurons and vascular endothelial cells in the brain, thereby constructing the elaborate networks of the tripartite synapse and the neurovascular unit, respectively. In addition to supporting neurons, glial cells modify synaptic plasticity and vascular tone, and in this way play an important role in maintaining brain homeostasis. Upon activation, glial cells produce nitric oxide, a gaseous mediator that diffuses into neighboring cells, wherein it elicits signaling pathways critical for synaptic plasticity and vascular tone. Because nitric oxide is short-lived and can travel only a short distance, glial cells must migrate to and position themselves near the target cells with which glial nitric oxide primarily interacts. Integrins, an essential family of cell adhesion molecules, facilitate effective glial migration and adhesion in the brain during developmental and normal adult stages. Aberrant regulation of nitric oxide and integrins in glial cells is thought to compromise cognitive brain function, and thereby lead to various pathologies. This review focuses on the important pathologic roles that nitric oxide and integrins play in glia and glia-related cells, focusing on their potential involvement in chronic pain syndrome.

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Glial TNFα in the Spinal Cord Regulates Neuropathic Pain Induced by HIV gp120 Application in Rats

Cited by 89 publications

References 61 publications

P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2′,3′-dideoxycytidine

P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2′,3′-dideoxycytidine

HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity

Integrins and Nitric Oxide in the Regulation of Glial Cells: Potential Roles in Pathological Pain

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