EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats.
Bidirectional signaling between ephrins and Eph receptor tyrosine kinases was first found to play important roles during development, but recently has been implicated in synaptic plasticity and pain processing in the matured nervous system. We show that ephrinB-EphB receptor signaling plays a critical role is induction and maintenance of neuropathic pain by regulating neural excitability and synaptic plasticity in the dorsal root ganglion (DRG) and the spinal dorsal horn (DH). Intrathecal application of blocking reagents for EphB-receptors, EphB1-Fc and EphB2-Fc chimeras inhibits the induction and maintenance of nerve injury-induced thermal hyperalgesia and mechanical allodynia. These blockers also prevent and suppress the nerve injury-induced hyperexcitability of nociceptive small DRG neurons, sensitization of DH neurons and long-term potentiation (LTP) of synapses between C fibers and DH neurons. In naïve, uninjured animals intrathecal administration of EphB-receptor activators ephrinB1-Fc and ephrinB2-Fc, respectively, induces thermal hypersensitivity and lowers the threshold for LTP, while EphB1-Fc prevents induction of the LTP. Western Blot analysis shows that nerve injury triggers an upregulation of the ephrinB1 and EphB1 receptor proteins in DRG and the spinal cord. These results indicate that, by regulating excitability of nociceptive-related neurons in DRG and DH and the synaptic plasticity at the spinal level, ephrinB-EphB receptor signaling contributes to neuropathic pain. This novel role for ephrinB-EphB receptor signaling suggests that these molecules may be useful therapeutic targets for treating pain after nerve injury.
Song
Xue-Jun
XJ
Department of Neurobiology, Parker University Research Institute, 2500 Walnut Hill Lane, Dallas, TX 75229, USA Jiangsu Province Key Laboratory of Anesthesiology and Center for Pain Research and Treatment, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
Zheng
Ji-Hong
JH
Cao
Jun-Li
JL
Liu
Wen-Tao
WT
Song
Xue-Song
XS
Huang
Zhi-Jiang
ZJ
D000818:Animals; D036387:Ephrin-B1 / Q000502:physiology*; D036388:Ephrin-B2 / Q000502:physiology*; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D009437:Neuralgia / Q000503:physiopathology*; D009473:Neuronal Plasticity / Q000502:physiology*; D010146:Pain / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D036081:Receptors, Eph Family / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
D036387:Ephrin-B1; D036388:Ephrin-B2; D036081:Receptors, Eph Family