EphrinB-EphB Signaling Induces Hyperalgesia through ERK5/CREB Pathway in Rats.

BACKGROUND There are numerous studies implicating that EphB receptors and ephrinB ligands play important roles in modulating the transduction of spinal nociceptive information. EphrinB-EphB signaling may contribute to hyperalgesia via various kinds of downstream molecules, the mechanisms of which have not been completely understood. OBJECTIVE The aim of the present study was to identify whether ephrinB-EphB signaling could contribute to hyperalgesia through ERK5/CREB pathway. STUDY DESIGN Controlled animal study. SETTING University laboratory. METHODS This study attempted to detect the changes of pain behaviors and the protein level of p-ERK5 and p-CREB by activating EphB receptors in the spinal cord of rats. To further confirm our hypothesis, we designed LV-siRNA for knockdown of spinal ERK5. When ERK5 was inhibited, we recorded the changes of spinal p-CREB expression and the pain behaviors of rats after activating EphB receptors. We also confirmed this conclusion in rat CCI model. Statistical analyses were performed using GraphPad Prism 5. RESULTS Intrathecal injection of ephrinB2-Fc in rats evoked thermal hyperalgesia and mechanical allodynia, along with activation of ERK5 and CREB in the spinal cord. Knockdown of ERK5 inhibited ephrinB2-Fc-induced CREB activation and hyperalgesia. Blocking EphB receptors prevented CCI-induced neuropathic pain and spinal ERK5/CREB activation. LIMITATIONS More underlying mechanisms that underlie the relationship between ephrinB-EphB signaling and ERK5/CREB pathway will need to be explored in future studies. CONCLUSIONS Our study suggests that ERK5/CREB pathway plays important roles in the transduction of nociceptive information associated with ephrinB-EphB signaling. This study provides further understanding of the downstream mechanisms of ephrinB-EphB signaling and helps to explore new targets for treating pathological pain.