Activation of EphB receptors contributes to primary sensory neuron excitability by facilitating Ca2+ influx directly or through Src kinase-mediated N-methyl-D-aspartate receptor phosphorylation

EphrinB-EphB receptor tyrosine kinases have been demonstrated to play important roles in pain processing after peripheral nerve injury. We have previously reported that ephrinB-EphB receptor signaling can regulate excitability and plasticity of neurons in spinal dorsal horn, and thus contribute to spinal central sensitization in neuropathic pain. How EphB receptor activation influences excitability of primary neurons in dorsal root ganglion (DRG), however, remains unknown. Here, we report that EphB receptor activation facilitates calcium influx through N-methyl-D-aspartate receptor (NMDAR) dependent and independent manners. In cultured DRG cells from adult rats, EphB1 and EphB2 receptors were expressed in neurons, but not the glial cells. Bath application of EphB receptor agonist ephrinB2-Fc induced NMDAR-independent Ca2+ influx, which was from the extracellular space rather than endoplasmic reticulum. EphB receptor activation also greatly enhanced NMDAR-dependent Ca2+ influx and NR2B phosphorylation, which was prevented by pretreatment of Src kinase inhibitor PP2. In nerve-injured DRG neurons, elevated expression and activation of EphB1 and EphB2 receptors contributed to the increased intracellular Ca2+ concentration and NMDA-induced Ca2+ influx. Repetitive intrathecal administration of EphB2-Fc inhibited the increased phosphorylation of NR2B and Ca2+-dependent subsequent signals Src, ERK, and CaMKII as well as behaviorally expressed pain after nerve injury. These findings d...
Source: Pain - Category: Anesthesiology Tags: Research Paper Source Type: research