Open AccessEphrinB-EphB Signaling Induces Hyperalgesia through ERK5/CREB Pathway in Rats
Author(s) -
Yu Lu,
Lihong Sun,
Min Wang,
Lieju Wang,
Ying Wu,
Jing Yu,
Wenna Wang,
Fengjiang Zhang,
Xue Li,
Min Yan
Publication year - 2017
Publication title -
pain physician
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.31
H-Index - 99
eISSN - 2150-1149
pISSN - 1533-3159
DOI - 10.36076/ppj.2017.e574
Subject(s) - creb , hyperalgesia , signal transduction , nociception , medicine , receptor , gene knockdown , spinal cord , neuropathic pain , neuroscience , allodynia , microbiology and biotechnology , pharmacology , biology , cell culture , transcription factor , biochemistry , genetics , gene
Background: There are numerous studies implicating that EphB receptors and ephrinBligands play important roles in modulating the transduction of spinal nociceptive information.EphrinB-EphB signaling may contribute to hyperalgesia via various kinds of downstreammolecules, the mechanisms of which have not been completely understood.Objective: The aim of the present study was to identify whether ephrinB-EphB signalingcould 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 proteinlevel of p-ERK5 and p-CREB by activating EphB receptors in the spinal cord of rats. To furtherconfirm our hypothesis, we designed LV-siRNA for knockdown of spinal ERK5. When ERK5 wasinhibited, we recorded the changes of spinal p-CREB expression and the pain behaviors of ratsafter activating EphB receptors. We also confirmed this conclusion in rat CCI model. Statisticalanalyses were performed using GraphPad Prism 5.Results: Intrathecal injection of ephrinB2-Fc in rats evoked thermal hyperalgesia andmechanical allodynia, along with activation of ERK5 and CREB in the spinal cord. Knockdownof ERK5 inhibited ephrinB2-Fc-induced CREB activation and hyperalgesia. Blocking EphBreceptors prevented CCI-induced neuropathic pain and spinal ERK5/CREB activation.Limitations: More underlying mechanisms that underlie the relationship between ephrinBEphB 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 thetransduction of nociceptive information associated with ephrinB-EphB signaling. This studyprovides further understanding of the downstream mechanisms of ephrinB-EphB signaling andhelps to explore new targets for treating pathological pain.Key words: EphrinB-EphB signaling, MAPK, ERK5, CREB, hyperalgesia, pain, CCI, NMDA