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NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphorylation

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Abstract

At present, chronic post-surgical pain (CPSP) is difficult to prevent and cure clinically because of our lack of understanding of its mechanisms. Surgical injury induces the upregulation of voltage-gated sodium channel Nav1.7 in dorsal root ganglion (DRG) neurons, suggesting that Nav1.7 is involved in the development of CPSP. However, the mechanism leading to persistent dysregulation of Nav1.7 is largely unknown. Given that nerve growth factor (NGF) induces a long-term increase in the neuronal hyperexcitability after injury, we hypothesized that NGF might cause the long-term dysregulation of Nav1.7. In this study, we aimed to investigate whether Nav1.7 regulation by NGF is involved in CPSP and thus contributes to the specific mechanisms involved in the development of CPSP. Using conditional nociceptor-specific Nav1.7 knockout mice, we confirmed the involvement of Nav1.7 in NGF-induced pain and identified its role in the maintenance of pain behavior during long-term observations (up to 14 days). Using western blot analyses and immunostaining, we showed that NGF could trigger the upregulation of Nav1.7 expression and thus support the development of CPSP in rats. Using pharmacological approaches, we showed that the increase of Nav1.7 might be partly regulated by an NGF/TrkA-SGK1-Nedd4-2-mediated pathway. Furthermore, reversing the upregulation of Nav1.7 in DRG could alleviate spinal sensitization. Our results suggest that the maintained upregulation of Nav1.7 triggered by NGF contributes to the development of CPSP. Attenuating the dysregulation of Nav1.7 in peripheral nociceptors may be a strategy to prevent the transition from acute post-surgical pain to CPSP.

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Abbreviations

CPSP:

chronic post-surgical pain

Navs:

voltage-gated sodium channels

NGF:

nerve growth factor

DRG:

dorsal root ganglion

PTM:

post-translational modification

Nedd4-2:

neuronal precursor cell-expressed developmentally downregulated 4-2

SGK1:

serum and glucocorticoid-inducible kinase

cKO:

conditional knock-out

SMIR:

skin/muscle incision and retraction

PWT:

paw withdrawal threshold

DMSO:

dimethyl sulfoxide

PLC-γ:

phospholipase C-γ

MAPK:

mitogen-activated protein kinase

PI3K:

phosphatidylinositol 3-kinase

VGLUT2:

vesicular glutamate transporter 2

BDNF:

brain-derived neurotrophic factor

CCL21:

chemokine ligand 21

TrkB:

tyrosine kinase receptor B

CGRP:

calcitonin gene-related peptide

TRPV:

transient receptor potential vanilloid family member

NMDA:

N-methyl-D-aspartate receptor

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

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Acknowledgments

We thank Professor Stephen G. Waxman (Yale University School of Medicine, USA) for kindly providing Nav1.7 cKO mice. We would like to thank Editage (www.editage.cn) for the English language editing.

Availability of Data and Material

All data of the study can be acquired from corresponding author through email.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant number: 81271235).

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Authors and Affiliations

  1. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Bao-Wen Liu, Jin Zhang, Yi-Shun Hong, Ning-Bo Li, Yi Liu, Mi Zhang, Wen-Yao Wu, Hua Zheng & Xian-Wei Zhang

  2. Institute of Physiology, Medical Faculty, RWTH Aachen University, Aachen, Germany

    Angelika Lampert

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  1. Bao-Wen Liu
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  2. Jin Zhang
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Contributions

Study concept and supervision: X.W.Z; study design: X.W.Z and B.W.L; acquisition and analysis: B.W.L, J.Z, Y.S.H, N.B.L, Y.L, M.Z, W.Y.W and H.Z; manuscript preparation: X.W.Z, B.W.L, and A.L.

Corresponding author

Correspondence to Xian-Wei Zhang.

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The authors declare that they have no conflict of interest.

Ethics Approval

All experiments were approved by the ethical committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (IRB ID: TJ-A20180801) and were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and followed the guidelines of the International Association for the Study of Pain.

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Liu, BW., Zhang, J., Hong, YS. et al. NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphorylation. Mol Neurobiol 58, 964–982 (2021). https://doi.org/10.1007/s12035-020-02156-1

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