NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphorylation
| Autor: | Angelika Lampert, Yishun Hong, Mi Zhang, Wenyao Wu, Xianwei Zhang, Jin Zhang, Yi Liu, Ningbo Li, Baowen Liu, Hua Zheng |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
business.industry Neuroscience (miscellaneous) Tropomyosin receptor kinase A 03 medical and health sciences Cellular and Molecular Neuroscience 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Nerve growth factor nervous system Neurology Dorsal root ganglion Downregulation and upregulation Knockout mouse medicine SGK1 Nociceptor business Neuroscience 030217 neurology & neurosurgery Sensitization |
| Zdroj: | Molecular Neurobiology. 58:964-982 |
| ISSN: | 1559-1182 0893-7648 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink