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.