NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphory
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NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphorylation Bao-Wen Liu 1 & Jin Zhang 1 & Yi-Shun Hong 1 & Ning-Bo Li 1 & Yi Liu 1 & Mi Zhang 1 & Wen-Yao Wu 1 & Hua Zheng 1 & Angelika Lampert 2 & Xian-Wei Zhang 1 Received: 19 May 2020 / Accepted: 29 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Chronic post-surgical pain . Nav1.7 . NGF . p-Nedd4-2 . SGK1
Introduction Currently, chronic post-surgical pain (CPSP) is still hard to prevent and cure in clinic and has a strong effect on the quality of life of patients [1, 2]. According to epidemiology, there are many risk factors associated with the incidence and severity of CPSP, including preoperative, intraoperative, and postoperative factors [2]. Since the mechanisms for pain chronification after surgery are complicated, the pathogenesis underlying the transition of acute post-surgical pain to CPSP is not entirely * Xian-Wei Zhang [email protected] 1
Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2
Institute of Physiology, Medical Faculty, RWTH Aachen University, Aachen, Germany
clear to date. However, it is generally believed that peripheral sensitization caused by surgical injury is the primary fa
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