1. 2017;20;E563-E574EphrinB-EphB Signaling Induces Hyperalgesia through ERK5/CREB Pathway in Rats
   Animal Study
   Min Yan, MD, Xue Li, MD, Feng-Jiang Zhang, MD, Wen-Na Wang, MD, Jing Yu, MS, Ying Wu, MS, Lie-Ju Wang, MS, Min Wang, MD, Li-Na Yu, MD, and Li-Hong Sun, MS.

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.