Involvement of EphB1 Receptor/EphrinB2 Ligand in Neuropathic Pain

Kobayashi, Hideo; Kitamura, Toshio; Sekiguchi, Miho; Homma, Miwako K.; Kabuyama, Yukihito; Konno, Satoshi; Kikuchi, Shinichi; Homma, Yoshimi

doi:10.1097/brs.0b013e318074d46a

Cited by 57 publications

(74 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). Intrathecal administration of ephrinB2-Fc chimera to Wistar rats induced behavioral evidence of thermal hyperalgesia (35).…”

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

View full text Add to dashboard Cite

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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Overexpression of EphB2 is correlated with a higher degree of pain, the mechanism for which is not yet apparent. 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

View full text Add to dashboard Cite

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.

show abstract

“…Recently, our and other studies also demonstrated that activation of spinal ephrinBs/EphBs system played a critical role in the development and maintenance of chronic pain after peripheral nerve injury (18)(19)(20)(21)(22). There are striking similarities between neuropathic pain and opiate dependence and tolerance, and neuropathic pain and opiate dependence may share some common mechanisms (23,24).…”

mentioning

confidence: 92%

Activation of Spinal EphrinBs/EphBs Contributes to Morphine Dependence and Tolerance

Li¹,

Ling²,

Yuan³

et al. 2014

J Anesth Perioper Med

View full text Add to dashboard Cite

Background: Previous studies have demonstrated that spinal ephrinBs/EphBs system plays a critical role in the development and maintenance of chronic pain, and neuropathic pain and opiate dependence may share some common mechanisms. The aim of this study was to further explore the role of the spinal ephrinBs/EphBs system in opiate dependence and tolerance. Methods: Adult male kunming mice were randomly allocated into treatment group and control group. Four different models including acute/chronic morphine dependence and acute/chronic morphine tolerance were set up in treatment group and control group individually. Withdrawal syndromes were precipitated by naloxone (4mg/ kg, intraperitoneal), the inhibitory or reversal role of EphB1-Fc in acute/chronic morphine withdrawal or tolerance was assessed by injecting 0.5 μg/5 μl EphB1-Fc intrathecally prior to the treatment of morphine. In control group, equal value of vehicle (saline) was substituted for morphine. In behavior part, morphine physical dependence was assessed by "withdrawal jumping" counting; and morphine induced antinociceptive tolerance was evaluated by "paw withdrawal latency" in hot-plate test. P-ERK and C-Fos expression in the spinal cord were detected by western blot and immunohistochemistry individually. Results: Acute and chronic morphine treatment increased the expression of spinal ephrinB1, which was further increased by acute morphine withdrawal precipitated by administration of naloxone; however, chronic morphine withdrawal precipitated by administration of naloxone decreased the expression of ephrinB1, which was significantly higher than that in saline group. Intrathecal pretreatment of EphB1-Fc inhibited or reversed morphine tolerance-induced antinociceptive tolerance and naloxoneprecipitated withdrawal jumping, which was accompanied with the decreased expression of spinal Fos protein and p-ERK. Conclusions: These results demonstrated that activation of spinal ephrinBs/EphBs contributed to morphine dependence and tolerance.

show abstract

Involvement of EphB1 Receptor/EphrinB2 Ligand in Neuropathic Pain

Cited by 57 publications

References 16 publications

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

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

Activation of Spinal EphrinBs/EphBs Contributes to Morphine Dependence and Tolerance

Contact Info

Product

Resources

About