Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model

Yan Fu; Liting Sun; Fengting Zhu; Wei Xia; Ting Wen; Ruilong Xia; Xin Yu; Dan Xu; Changgeng Peng

doi:10.3389/fnmol.2023.1091096

Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model

Front Mol Neurosci. 2023 Mar 3:16:1091096. doi: 10.3389/fnmol.2023.1091096. eCollection 2023.

Authors

Yan Fu^{1

2}, Liting Sun², Fengting Zhu^{2

3}, Wei Xia², Ting Wen², Ruilong Xia², Xin Yu³, Dan Xu¹, Changgeng Peng²

Affiliations

¹ Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, Shanghai, China.
² The First Rehabilitation Hospital of Shanghai, Brain and Spinal Cord Innovation Research Center, School of Medicine, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China.
³ Pre-clinical College, Dali University, Dali, Yunnan, China.

Abstract

Neuropathic pain (NP) induced by spinal cord injury (SCI) often causes long-term disturbance for patients, but the mechanisms behind remains unclear. Here, our study showed SCI-induced ectopic expression of Nav1.7 in abundant neurons located in deep and superficial laminae layers of the spinal dorsal horn (SDH) and upregulation of Nav1.7 expression in dorsal root ganglion (DRG) neurons in mice. Pharmacologic studies demonstrated that the efficacy of the blood-brain-barrier (BBB) permeable Nav1.7 inhibitor GNE-0439 for attenuation of NP in SCI mice was significantly better than that of the BBB non-permeable Nav1.7 inhibitor PF-05089771. Moreover, more than 20% of Nav1.7-expressing SDH neurons in SCI mice were activated to express FOS when there were no external stimuli, suggesting that the ectopic expression of Nav1.7 made SDH neurons hypersensitive and Nav1.7-expressing SDH neurons participated in central sensitization and in spontaneous pain and/or walking-evoked mechanical pain. Further investigation showed that NGF, a strong activator of Nav1.7 expression, and its downstream JUN were upregulated after SCI in SDH neurons with similar distribution patterns and in DRG neurons too. In conclusion, our findings showed that the upregulation of Nav1.7 was induced by SCI in both SDH and DRG neurons through increased expression of NGF/JUN, and the inhibition of Nav1.7 in both peripheral and spinal neurons alleviated mechanical pain in SCI mice. These data suggest that BBB permeable Nav1.7 blockers might relieve NP in patients with SCI and that blocking the upregulation of Nav1.7 in the early stage of SCI via selective inhibition of the downstream signaling pathways of NGF or Nav1.7-targeted RNA drugs could be a strategy for therapy of SCI-induced NP.

Keywords: FOS; JUN; NGF; Nav1.7; neuropathic pain; spinal cord injury.