EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats

Song, Xue-Jun; Zheng, Jihong; Cao, Jun‐Li; Li, Wentao; Song, Xuesong; Huang, Zhi-Jiang

doi:10.1016/j.pain.2008.03.019

Cited by 93 publications

(131 citation statements)

References 51 publications

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“…WNT agonist-induced thermal and mechanical hypersensitivity, the values represent the mean of both feet of the rat. The protocols used for determining the pain-related behaviors are similar to those we have previously described (38,49,50).…”

Section: Methodsmentioning

confidence: 99%

WNT signaling underlies the pathogenesis of neuropathic pain in rodents

Zhang

Huang²,

Liu³

et al. 2013

J. Clin. Invest.

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186

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Treating neuropathic pain is a major clinical challenge, and the underlying mechanisms of neuropathic pain remain elusive. We hypothesized that neuropathic pain-inducing nerve injury may elicit neuronal alterations that recapitulate events that occur during development. Here, we report that WNT signaling, which is important in developmental processes of the nervous system, plays a critical role in neuropathic pain after sciatic nerve injury and bone cancer in rodents. Nerve injury and bone cancer caused a rapid-onset and long-lasting expression of WNTs, as well as activation of WNT/frizzled/β-catenin signaling in the primary sensory neurons, the spinal dorsal horn neurons, and astrocytes. Spinal blockade of WNT signaling pathways inhibited the production and persistence of neuropathic pain and the accompanying neurochemical alterations without affecting normal pain sensitivity and locomotor activity. WNT signaling activation stimulated production of the proinflammatory cytokines IL-18 and TNF-α and regulated the NR2B glutamate receptor and Ca 2+ -dependent signals through the β-catenin pathway in the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the WNT signaling pathway may be an effective approach for treating neuropathic pain, including bone cancer pain.

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Section: Methodsmentioning

confidence: 99%

WNT signaling underlies the pathogenesis of neuropathic pain in rodents

Zhang

Huang²,

Liu³

et al. 2013

J. Clin. Invest.

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186

202

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“…Intrathecal administration of ephrinB2-Fc chimera to Wistar rats induced behavioral evidence of thermal hyperalgesia (35). Conversely, pharmacological antagonization of EphB1 prevented nerve injury-induced dorsal horn neuron hyperexcitability and neuropathic pain (37). Not only in somatic pain caused by injury or inflammation, our study investigating cross talk between pelvic viscera has demonstrated that acute activation of transient receptor potential vanilloid 1 expressing nociceptive afferent fibers coming from the descending colon upregulated spinal ephrinB2 expression and simultaneously induced EphB1/2 phosphorylation in the lumbosacral dorsal horn (28).…”

Section: F408mentioning

confidence: 98%

“…Following nerve injury, the expression of ephrinB2 in dorsal root ganglion (DRG) neurons and the EphB1 receptor in the dorsal horn were both enhanced in a time-dependent manner corresponding to the development of thermal hyperalgesia in adult rats (36,37). Knock-down of ephrinB2 using specific short interfering RNA decreased expression of ephrinB2 in the DRG, along with attenuation of mechanical allodynia caused by spinal nerve crushing (13).…”

Section: F408mentioning

confidence: 99%

EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B

Chang

Peng

et al. 2011

American Journal of Physiology-Renal Physiology

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Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in painrelated neural plasticity at the spinal cord level have been identified. To test whether Src-family tyrosine kinase-dependent glutamatergic N-methyl-D-aspartate receptor NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate pelvic-urethra reflex potentiation, we recorded external urethra sphincter electromyogram reflex activity and analyzed protein expression in the lumbosacral (L6-S2) dorsal horn in response to intrathecal ephrinB2 injections. When compared with vehicle solution, exogenous ephrinB2 (5 g/rat it)-induced reflex potentiation, in associated with phosphorylation of EphB1/2, Src-family kinase, NR2B Y1336 and Y1472 tyrosine residues. Both intrathecal EphB1 and EphB2 immunoglobulin fusion protein (both 10 g/rat it) prevented ephrinB2-dependent reflex potentiation, as well as protein phosphorylation. Pretreatment with PP2 (50 M, 10 l it), an Src-family kinase antagonist, reversed the reflex potentiation, as well as Src kinase and NR2B phosphorylation. Together, these results suggest the ephrinB2-dependent EphBR activation, which subsequently provokes Src kinase-mediated N-methyl-D-aspartate receptor NR2B phosphorylation in the lumbosacral dorsal horn, is crucial for the induction of spinal reflex potentiation contributing to the development of visceral pain and/or hyperalgesia in the pelvic area. pelvic pain; urethra; Src-family kinase; N-methyl-D-aspartate IN THE LUMBOSACRAL DORSAL horn, neurotransmission mediated by glutamatergic N-methyl-D-aspartate receptors (NMDARs) has been implicated in processing nociceptive afferent inputs coming from the lower urinary tract (4, 10). Spinal administration of NMDAR agonists has dose-dependently facilitated the visceromotor reflex, together with pressor responses to pelvic noxious stimulation (14). Conversely, blockage of NMDAR using pharmacological antagonists has inhibited pain behavior caused by irritation of the pelvic viscera (24, 43). Among subunits of NMDAR, the role of the NR2B subunit in pain development has been intensively investigated, as electrophysiological studies have demonstrated that phosphorylation of specific NR2B tyrosine residues is an important determinant for NMDAR-mediated currents (22), which defines the role of NMDARs in pain-related neural plasticity (3,17,18,20). The signaling of Src kinases, a family of protooncogenic tyrosine kinases, has been shown to modulate NMDAR-mediated synaptic transmission and plasticity (1). In inflammatory animal models, the intrathecal administration of Src-family kinase inhibitors prevented spinal NR2B phosphorylation and behavior hyperalgesia, implying that Src-dependent phosphorylation of NMDAR NR2B subunits plays a crucial role in the development of postinflammatory pain and/or hyperalgesia (35).EphB receptors (EphBRs), transmembrane molecules, were initially identified as guidance cues during neural development (40). In the last decade, studies have demonstrated that the intera...

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“…However, the ephrin-B-EphB receptor signalling has been shown to contribute to neuropathic pain by regulating excitability of nociceptive-related neurons in dorsal root ganglion and dorsa horn and the synaptic plasticity at the spinal level (15). Moreover, ephrin-B2 siRNA may be a potential therapeutic agent for neuropathic pain (16).…”

Section: -B2 --------------------------------------------------------mentioning

confidence: 99%

Overexpression of the B-type Eph and ephrin genes correlates with progression and pain in human pancreatic cancer

Lu¹,

Zhang²,

Li³

et al. 2012

Oncology Letters

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Abstract. B-type erythropoietin-producing hepatocellular (EphB) receptors and their ephrin ligands are associated with aggressive behavior and poor prognosis in a number of malignancies. The aim of this study was to determine the association between the aberrant expression of these genes and prognosis in human pancreatic cancer. The expression of EphB and the ephrin ligands was determined using real-time quantitative reverse transcription PCR in 46 human primary pancreatic cancers. Overexpression of EphB2 and a more modest overexpression of ephrin-B2 mRNA were observed in more than 44% (20/46) of the pancreatic cancer specimens examined. Overexpression (>upper quartile) of EphB2 and ephrin-B2 was markedly associated with abdominal and/or back pain. Multivariate analysis identified the overexpression of EphB2 as an independent prognostic factor for disease-free and overall survival (both P<0.05). The results of the present study suggest that an increased level of ephrin-B2, in the presence of a high expression of EphB2, leads to a more aggressive tumor phenotype and that EphB2 may be used as a prognostic factor in human pancreatic cancer.

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EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats

Cited by 93 publications

References 51 publications

WNT signaling underlies the pathogenesis of neuropathic pain in rodents

WNT signaling underlies the pathogenesis of neuropathic pain in rodents

EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B

Overexpression of the B-type Eph and ephrin genes correlates with progression and pain in human pancreatic cancer

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