BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation

Ding, Xu; Cai, Jie; Li, Song; Liu, Xiaodan; Wan, You; Xing, Guo-Gang

doi:10.1016/j.nbd.2014.10.025

Cited by 55 publications

(53 citation statements)

References 160 publications

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“…Mechanical hypersensitivity, as a behavioral sign of bone cancer pain, was assessed by measuring 50% PWT as described in our previous reports (59,60). The 50% PWT in response to a series of von Frey filament (Stoelting, Wood Dale, IL) was determined by the up-and-down method (61).…”

Section: Behavioral Testsmentioning

confidence: 99%

Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis

Yang

Jin

et al. 2018

Sci. Signal.

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Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and cancer-associated pain. Overexpressing TRESK in DRG neurons suppressed tumor-induced neuronal hyperexcitability and pain hypersensitivity in bone metastasis model rats, whereas knocking down TRESK increased neuronal hyperexcitability and pain hypersensitivity in normal rats. Mechanistically, tumor-associated production of vascular endothelial growth factor (VEGF) activated the receptor VEGFR2 on DRGs, which increased the abundance of the calcineurin inhibitor DSCR1, which, in turn, decreased calcineurin-mediated activation of the transcription factor NFAT, thereby reducing the transcription of the gene encoding TRESK. Intrathecal application of exogenous calcineurin to tumor-bearing rats rescued TRESK abundance and abrogated both DRG hyperexcitability and pain hypersensitivity, whereas either inhibition or knockdown of calcineurin in normal rats reduced TRESK abundance and increased DRG excitability and pain sensitivity. These findings identify a potentially targetable mechanism that may cause bone metastasis–associated pain in cancer patients.

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Section: Behavioral Testsmentioning

confidence: 99%

Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis

Yang

Jin

et al. 2018

Sci. Signal.

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“…The fact that chronic ketamine treatment prevented the mechanical hyperalgesia induced by intrathecal BDNF is consistent with previous observations indicating that spinal NMDA receptors, downstream to TrkB signalling, are importantly involved in the behavioural expression of BDNF‐induced central sensitization underlying some chronic pain conditions. In this regard, it has been reported that, in the spinal cord, BDNF triggers phosphorylation of NMDA receptor subunits NR1 (Slack et al., ; Liu et al., ) and NR2B (Ding et al., ) leading to the induction of late, protein‐dependent long‐term potentiation (LTP) in dorsal horn neurons (Zhou et al., ; Liu and Zhou, ), and that these events are mechanistically associated with behavioural pain responsiveness in neuropathic experimental models of chronic pain (Geng et al., ; Ding et al., ). Nevertheless, the anti‐hyperalgesic effect of ketamine on the paw pressure threshold of BDNF‐injected rats was transient and reversible, as indicated by the appearance of mechanical hyperalgesia once the ketamine pump was depleted.…”

Section: Discussionmentioning

confidence: 99%

“…Binding of BDNF to the TrkB receptor cytoplasmic region promotes the activation of the signalling pathways RAS‐ERK, P13K‐Akt and PLCγ1‐PKC (Khan and Smith, ). In adult neurons, activation of these pathways regulates neural response and synaptic function in the dorsal horn output neurons through a variety of neuroplasticity mechanisms (Smith, ), including increased phosphorylation of NMDA receptor subunits NR1 (Slack et al., ; Liu et al., ) and NR2B (Ding et al., ), leading to the induction of late, protein‐dependent long‐term potentiation (LTP) in dorsal horn neurons (Zhou et al., ; Liu and Zhou, ). As a whole, these neuroplastic changes could mechanistically explain BDNF‐mediated central sensitization and the related development of chronic pain.…”

Section: Introductionmentioning

confidence: 99%

Role of the spinal TrkB‐NMDA receptor link in the BDNF‐induced long‐lasting mechanical hyperalgesia in the rat: A behavioural study

Marcos

Galleguillos²,

Hernández³

et al. 2017

European Journal of Pain

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“…Cultured microglias or astrocytes were lysed [31] and commercially available ELISA kits were applied to explore the expression of CD11b (Cloud-Clone Corp., Houston, TX, USA) and glial fibrillary acidic protein (GFAP) (Abcam, Cambridge, MA, USA) following manufacturer's instructions. The concentrations of CD11b and GFAP were normalized to the amount of total protein in rat microglias and astrocytes.…”

Section: Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

Serum IgG-indcued microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

Ding

Yang

et al. 2020

Preprint

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BackgroundOpsoclonus-myoclonus syndrome (OMS) is a rare neurological disease. Some children with OMS also have neuroblastoma (NB). We and others have previously documented that serum IgG from children with OMS and NB induces neuronal cytolysis via several signaling pathways. However, mechanisms underlying OMS remain unclear. Here we investigated whether nitric oxide (NO) from activated microglias and its cascade contribute to neuronal cytolysis in pediatric OMS. MethodsThe activation of cultured cerebral cortical and cerebellar microglias incubated with sera or IgG isolated from sera of children with OMS and NB was measured by the expression of the activation marker, cytokines and NO. Neuronal cytolysis was determined after exposing to IgG-treated microglia conditioned media. Using inhibitors and activators, the effects of NO synthesis and its intracellular cascade, namely soluble guanylyl cyclase (sGC) and protein kinase G (PKG), on neuronal cytolysis were evaluated. ResultsIncubation with sera or IgG from children with OMS and NB increased the activation of cerebral cortical and cerebellar microglias, but not the activation of astrocytes or the cytolysis of glial cells.Moreover, the cytolysis of neurons was elevated by conditioned media from microglias incubated with IgG from children with OMS and NB, which was relieved by the inhibitors of NO signaling. By contrast, neuronal cytolysis was exacerbated by the activators of NO signaling but not proinflammatory cytokines. Neuronal cytolysis was suppressed by pretreatment with the microglial inhibitor minocycline, a clinically tested drug. Finally, increased microglial activation did not depend on the Fab fragment of serum IgG. ConclusionsSerum IgG from children with OMS and NB potentiates microglial activation, which induces neuronal cytolysis through the NO/sGC/PKG pathway, suggesting an applicability of microglial inhibitor as a therapeutic candidate. BackgroundOpsoclonus-myoclonus syndrome (OMS) is a rare but devastating neurological disease, characterized by opsoclonus, myoclonus and ataxia. Most patients suffer from persistent deficits in cognition, neurology and behavior. Some children with OMS also have neuroblastoma (NB), although varied percentages have been reported [1][2][3][4][5]. Previously, we have documented that the insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase cascade alleviates neuronal cytolysis induced by serum IgG from children with OMS and NB [6], others also reported that the phosphorylation of extracellular signal-regulated kinase contributes to neuronal cytolysis in pediatric OMS [7]. Yet, the cellular and molecular mechanisms associated with neuronal cytolysis underlying pediatric OMS remain unclear. Microglias are major immune effectors in the central nervous system (CNS) and have an important physiological function in inflammation [8]. Notably, patients with pediatric OMS exhibit increased expression of a microglial marker and proinflammatory cytokines in cerebrospinal fluid (CSF) and some children with OMS are post-inf...

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BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation

Cited by 55 publications

References 160 publications

Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis

Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis

Role of the spinal TrkB‐NMDA receptor link in the BDNF‐induced long‐lasting mechanical hyperalgesia in the rat: A behavioural study

Serum IgG-indcued microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

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