Blockade of Spinal EphA4 Reduces Chronic Inflammatory Pain in Mice

ABSTRACT

Background: Erythropoietin-producing hepatocellular (Ephs) receptor and their ligands, ephrins, orchestrate the induction of cell proliferation and migration, axonal guidance, synaptic genesis and synaptic plasticity in the central nervous system. Previous studies demonstrated that EphBs/ephrinBs participate in the pathophysiology of neuropathic pain, inflammatory pain and bone cancer pain, but the role of EphA4 in the regulation of pain in the spinal cord is unknown. Therefore, we explored the role of EphA4 receptor in regulating chronic inflammatory pain.

Methods: We established a mouse model of chronic inflammatory pain through plantar injection of complete freund’s adjuvant (CFA) and assessed EphA4 expression in spinal cord by western blotting. EphA4 receptor was blocked by intrathecal injection of EphA4-Fc, an EphA4 antagonist, and pain behaviors were measured by assessing thermal hyperalgesia and mechanical allodynia. Finally, immunohistochemistry was performed to analyze the changes in the expression of Fos protein in spinal cord after blocking EphA4 receptor.

Results: Plantar injection of CFA produced persistent thermal hyperalgesia and mechanical allodynia, which was accompanied by significant increases in spinal EphA4 and Fos expression. Blocking spinal EphA4 receptor suppressed CFA-induced pain behaviors and reduced the expression of Fos protein in spinal cord.

Conclusions: Our study demonstrated that EphA4 receptor is involved in the generation and maintenance of CFA-induced chronic inflammatory pain and that blocking the spinal EphA4 receptor could relieve persistent pain behaviors in mice.

KEYWORDS:

• EphA4 receptor
• complete freund’s adjuvant
• chronic inflammatory pain
• thermal hyperalgesia
• mechanical allodynia

Acknowledgments

Authors thank the Natural Science Foundation of Taizhou People’s Hospital (grant number: ZL201825) for financial and experimental technique support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Notes on contributors

Yin Wang

Yin Wang, graduated from Xuzhou Medical University of China with a master’s degree. His research direction is pain signal transduction and regulation.

Chuanyun Wen

Chuanyun Wen, graduated from Xuzhou Medical University of China with a master’s degree. Her research direction is pain signal transduction and regulation.

Guozhu Xie

Guozhu Xie, graduated from Yangzhou Medical University of China with a master’s degree. His research direction is pain signal transduction and regulation.

Lin Jiang

Lin Jiang, graduated from Nanjing Medical University of China with a master’s degree. Her research direction is perioperative medicine.