Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Institute of Physiology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Mol Neurobiol. 2021 Mar;58(3):964-982. doi: 10.1007/s12035-020-02156-1. Epub 2020 Oct 16.
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.
目前，由于我们对其机制缺乏了解，慢性术后疼痛（CPSP）临床上难以预防和治疗。手术损伤诱导背根神经节（DRG）神经元中电压门控钠通道 Nav1.7 的上调，表明 Nav1.7 参与了 CPSP 的发展。然而，导致 Nav1.7 持续失调的机制在很大程度上尚不清楚。鉴于神经生长因子（NGF）在损伤后会引起神经元过度兴奋的长期增加，我们假设 NGF 可能导致 Nav1.7 的长期失调。在这项研究中，我们旨在研究 NGF 对 Nav1.7 的调节是否参与 CPSP，从而有助于阐明 CPSP 发展中涉及的特定机制。使用条件性伤害感受器特异性 Nav1.7 敲除小鼠，我们证实了 Nav1.7 在 NGF 诱导的疼痛中的作用，并确定了其在长期观察（长达 14 天）期间对疼痛行为维持中的作用。通过 Western blot 分析和免疫染色，我们表明 NGF 可以触发 Nav1.7 表达的上调，从而支持大鼠 CPSP 的发展。通过药理学方法，我们表明 Nav1.7 的增加可能部分受到 NGF/TrkA-SGK1-Nedd4-2 介导的途径调节。此外，逆转 DRG 中 Nav1.7 的上调可以减轻脊髓敏化。我们的结果表明，NGF 触发的 Nav1.7 的持续上调有助于 CPSP 的发展。减轻周围伤害感受器中 Nav1.7 的失调可能是预防急性术后疼痛向 CPSP 转变的一种策略。
