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

Abstract

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 demonstrate that activation of EphB receptors can modulate DRG neuron excitability by facilitating Ca2+ influx directly or through Src kinase activation-mediated NMDA receptor phosphorylation and that EphB receptor activation is critical to DRG neuron hyperexcitability, which has been considered critical to the subsequent spinal central sensitization and neuropathic pain.

Gut microbiota depletion by antibiotics ameliorates somatic neuropathic pain induced by nerve injury, chemotherapy, and diabetes in mice

“…Chronic constriction injury of the sciatic nerve (CCI) has been a widely used mode of neuropathic pain after peripheral nerve injury in rodents [ 15 ]. In brief, the left common sciatic nerve of each mouse employed was exposed at the mid-thigh level.…”

Lysophosphatidic acid receptor 1/3 antagonist inhibits the activation of satellite glial cells and reduces acute nociceptive responses

“…It was reported that 18:1 LPA as well as ATP and capsaicin, induced calcium (Ca 2+ ) mobilization, which depends on phospholipase C in cultured sensory neurons and SGCs 13 . Activation of ERK1/2 and the Ca 2+ mobilization is known to promote the transcriptional activity of CREB and involved in a variety of cellular processes such as neuron‐glia communication 36,41 . We detected a marked increase of LPA in the innervated DRG to the injured paw and increased ERK phosphorylation.…”

“…13 Activation of ERK1/2 and the Ca 2+ mobilization is known to promote the transcriptional activity of CREB and involved in a variety of cellular processes such as neuron-glia communication. 36,41 We detected a marked increase of LPA in the innervated DRG to the injured paw and increased ERK phosphorylation. Then, the subsequent phosphorylation of CREB in the DH of the spinal cord could lead to central sensitization.…”

Peripheral EphrinB1/EphB1 signalling attenuates muscle hyperalgesia in MPS patients and a rat model of taut band-associated persistent muscle pain

“…9 Eph enhanced the function of NMDA and upregulated its expression in the dorsal root ganglion, trigeminal ganglion or peripheral sensory neurons. 20,26 The ionic NMDA receptor is an important part of the nociceptive signalling mechanism in the spinal dorsal horn and peripheral sensory neurons, and it is closely related to the main mechanism of pain development. 27 Therefore, the Ephrin B/EphB signal may contribute to the sensitization of primary muscle afferents and the persistent muscle mechanical hyperalgesia observed in the present study.…”