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

Yi, Zhihua; Xie, Lihui; Zhou, Chi; Yuan, Huilong; Ouyang, Shuai; Fang, Zhi; Zhao, Shanhong; Jia, Tianyu; Zou, Lifang; Wang, Shouyu; Xue, Yun; Wu, Bing; Gao, Yun; Li, Guilin; Liu, Shuangmei; Xu, Hong; Xu, Changshui; Zhang, Chunping; Liang, Shangdong

doi:10.1007/s11302-017-9594-z

Cited by 29 publications

(15 citation statements)

References 47 publications

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“…Mounting evidence suggests that activation of satellite glial cells indeed participate in neuropathic pain. 39 – 41 Thus, the transient presence of ATF2 in these cells may have a role in neuropathic pain. Our data partially agree with other observations indicating that stimulation of adult DRG neurons by doxorubicin or ultraviolet irradiation ( in vitro ) and axotomy ( in vivo ) induce a rapid (2–24 h) and consistent (3–20 days) down-regulation of ATF2.…”

Section: Discussionmentioning

confidence: 99%

ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

et al. 2018

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Transcription factors are proteins that modulate the transcriptional rate of target genes in the nucleus in response to extracellular or cytoplasmic signals. Activating transcription factors 2 (ATF2) and 3 (ATF3) respond to environmental signals and maintain cellular homeostasis. There is evidence that inflammation and nerve injury modulate ATF2 and ATF3 expression. However, the function of these transcription factors in pain is unknown. The purpose of this study was to investigate the contribution of ATF2 and ATF3 to nerve injury-induced neuropathic pain. L5/6 spinal nerve ligation induced tactile allodynia and thermal hyperalgesia. Moreover, nerve damage enhanced ATF2 and ATF3 protein expression in injured L5/6 dorsal root ganglia and spinal cord but not in uninjured L4 dorsal root ganglia. Nerve damage also enhanced ATF2 immunoreactivity in dorsal root ganglia and spinal cord 7 to 21 days post-injury. Repeated intrathecal post-treatment with a small-interfering RNA targeted against ATF2 (ATF2 siRNA) or anti-ATF2 antibody partially reversed tactile allodynia and thermal hyperalgesia. In contrast, ATF3 siRNA or anti-ATF3 antibody did not modify nociceptive behaviors. ATF2 immunoreactivity was found in dorsal root ganglia and spinal cord co-labeling with NeuN mainly in non-peptidergic (IB4+) but also in peptidergic (CGRP+) neurons. ATF2 was found mainly in small- and medium-sized neurons. These results suggest that ATF2, but not ATF3, is found in strategic sites related to spinal nociceptive processing and participates in the maintenance of neuropathic pain in rats.

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Section: Discussionmentioning

confidence: 99%

ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

et al. 2018

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“…73 Another study demonstrated elevated expression of P2X3 protein in DRG in gp120-treated rats that correlated with neuropathic hypersensitivity sensitive to pharmacological antagonism of P2X3. 74,75 Upregulation of DRG expression of P2X7 has also been demonstrated following gp120 treatment. Subsequent treatment with the P2X7 antagonist, brilliant blue G, decreased hyperalgesia and P2X7 expression, and also decreased IL-1β and TNF-α receptor expression while increasing IL-10 in gp120-treated DRG.…”

Section: Mechanisms Of Chronic Pain In Hivmentioning

confidence: 95%

Chronic Pain in HIV

2020

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The evolution of therapeutics for and management of human immunodeficiency virus-1 (HIV-1) infection has shifted it from predominately manifesting as a severe, acute disease with high mortality to a chronic, controlled infection with a near typical life expectancy. However, despite extensive use of highly active antiretroviral therapy, the prevalence of chronic widespread pain in people with HIV remains high even in those with a low viral load and high CD4 count. Chronic widespread pain is a common comorbidity of HIV infection and is associated with decreased quality of life and a high rate of disability. Chronic pain in people with HIV is multifactorial and influenced by HIV-induced peripheral neuropathy, drug-induced peripheral neuropathy, and chronic inflammation. The specific mechanisms underlying these three broad categories that contribute to chronic widespread pain are not well understood, hindering the development and application of pharmacological and nonpharmacological approaches to mitigate chronic widespread pain. The consequent insufficiencies in clinical approaches to alleviation of chronic pain in people with HIV contribute to an overreliance on opioids and alarming rise in active addiction and overdose. This article reviews the current understanding of the pathogenesis of chronic widespread pain in people with HIV and identifies potential biomarkers and therapeutic targets to mitigate it.

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“…P2Y12 antagonism reduces pain by reducing microglial activation and p38 MAPK phosphorylation in a spinal nerve ligation neuropathic pain model (77). Similarly, the expression of P2Y12 receptor in peripheral satellite glia is also related to pain and its antagonism leads to reduced cytokine production and p38 MAPK phosphorylation and higher withdrawal thresholds (78). It has been demonstrated that in platelets activation of P2Y12 receptor occurs in lipid rafts (79,80).…”

Section: P2x and P2y Purinergic Receptorsmentioning

confidence: 99%

Lipid rafts in glial cells: role in neuroinflammation and pain processing

Miller

Navia-Pelaez

Corr

et al. 2020

Journal of Lipid Research

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Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.

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

Cited by 29 publications

References 47 publications

ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

Chronic Pain in HIV

Lipid rafts in glial cells: role in neuroinflammation and pain processing

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