Hu Tingting, Pang Miaoyi, Sun Qingyu, Gou Yu, Liu Jing, Wang Xiaotong, Ma Yiran, Chen Wen, Wei Chao, Liu Meng, Ding Yumeng, Zhang Yurui, Liu Dianxin, Wu Weihua, Wang Peipei, Zhu Hongwei, Li Qian, Yang Fei
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin 300222, China.
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
J Pain. 2025 May;30:105374. doi: 10.1016/j.jpain.2025.105374. Epub 2025 Mar 17.
Primary sensory neurons serve as a critical link between the peripheral nervous system (PNS) and the central nervous system (CNS). They represent the initial neural tissue responsible for transmitting sensations and pain. In case where peripheral nerves are injured, nerve fiber regeneration can lead to severe pain. Semaphorin3A (Sema3A), an axon guidance molecule that can be secreted by Schwann cells, has been shown to effectively inhibit the regeneration of embryonic and adult dorsal root ganglion (DRG). However, its role in neuropathic pain and the underlying mechanisms remain unexplored. This study employed a chronic constriction injury (CCI) model of neuropathic pain in mice. We observed that increased expression of Sema3A could alleviate both mechanical and heat nociceptive behaviors in model mice. By overexpressing Sema3A in ipsilateral DRG neurons via DRG injection, we found that the phosphorylation of the PI3K/Akt/mTOR signaling pathway and eukaryotic initiation factor 2α (eIF2α) was inhibited, thereby inhibiting pain. eIF2α is a translation initiation factor and its phosphorylation can regulate global translation. The inhibition of eIF2α phosphorylation through PKR and PERK inhibitors also reduced the expression of ion channels and ultimately alleviated neuropathic pain. We found that Sema3A could suppress the phosphorylation of eIF2α by inhibiting the PI3K/AKT/mTOR pathway, thus affecting pain perception. These findings suggested that alterations in Sema3A expression and eIF2α phosphorylation were involved in the development of neuropathic pain, providing potential new targets for clinical pain-relief drug development. PERSPECTIVE: The expression of Sema3A in DRG neurons was decreased following peripheral nerve injury. Elevating Sema3A levels alleviated neuropathic pain by inhibiting the PI3K/Akt/mTOR pathway and eIF2α phosphorylation, thus affecting ion channel expression in DRG of neuropathic pain model animals. This highlighted Sema3A as potential therapeutic targets for pain relief.
初级感觉神经元是外周神经系统（PNS）与中枢神经系统（CNS）之间的关键连接。它们是负责传递感觉和疼痛的初始神经组织。在外周神经受损的情况下，神经纤维再生会导致严重疼痛。信号素3A（Sema3A）是一种可由雪旺细胞分泌的轴突导向分子，已被证明能有效抑制胚胎和成年背根神经节（DRG）的再生。然而，其在神经性疼痛中的作用及潜在机制仍未被探索。本研究采用小鼠神经性疼痛的慢性压迫损伤（CCI）模型。我们观察到Sema3A表达增加可减轻模型小鼠的机械性和热伤害性感受行为。通过向同侧DRG神经元注射过表达Sema3A，我们发现PI3K/Akt/mTOR信号通路和真核起始因子2α（eIF2α）的磷酸化受到抑制，从而抑制疼痛。eIF2α是一种翻译起始因子，其磷酸化可调节整体翻译。通过PKR和PERK抑制剂抑制eIF2α磷酸化也可降低离子通道的表达，最终减轻神经性疼痛。我们发现Sema3A可通过抑制PI3K/AKT/mTOR通路抑制eIF2α的磷酸化，从而影响痛觉。这些发现表明Sema3A表达和eIF2α磷酸化的改变参与了神经性疼痛的发展，为临床镇痛药物开发提供了潜在的新靶点。观点：外周神经损伤后DRG神经元中Sema3A的表达降低。提高Sema3A水平可通过抑制PI3K/Akt/mTOR通路和eIF2α磷酸化来减轻神经性疼痛，从而影响神经性疼痛模型动物DRG中的离子通道表达。这突出了Sema3A作为疼痛缓解潜在治疗靶点的作用。
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