Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Cell Res. 2022 May;32(5):461-476. doi: 10.1038/s41422-022-00616-y. Epub 2022 Feb 3.
Both opioids and nonsteroidal anti-inflammatory drugs (NSAIDS) produce deleterious side effects and fail to provide sustained relief in patients with chronic inflammatory pain. Peripheral neuroinflammation (PN) is critical for initiation and development of inflammatory pain. A better understanding of molecular mechanisms underlying PN would facilitate the discovery of new analgesic targets and the development of new therapeutics. Emerging evidence suggests that peripheral sensory neurons are not only responders to painful stimuli, but are also actively engaged in inflammation and immunity, whereas the intrinsic regulatory mechanism is poorly understood. Here we report the expression of proton-selective ion channel Hv1 in peripheral sensory neurons in rodents and humans, which was previously shown as selectively expressed in microglia in mammalian central nervous system. Neuronal Hv1 was up-regulated by PN or depolarizing stimulation, which in turn aggravates inflammation and nociception. Inhibiting neuronal Hv1 genetically or by a newly discovered selective inhibitor YHV98-4 reduced intracellular alkalization and ROS production in inflammatory pain, mitigated the imbalance in downstream SHP-1-pAKT signaling, and also diminished pro-inflammatory chemokine release to alleviate nociception and morphine-induced hyperalgesia and tolerance. Thus, our data reveal neuronal Hv1 as a novel target in analgesia strategy and managing opioids-related side effects.
阿片类药物和非甾体抗炎药 (NSAIDs) 都会产生有害的副作用，并不能为慢性炎症性疼痛患者提供持续的缓解。周围神经炎症 (PN) 是炎症性疼痛发生和发展的关键。更好地了解 PN 的分子机制将有助于发现新的镇痛靶点和开发新的治疗方法。新出现的证据表明，周围感觉神经元不仅对疼痛刺激有反应，而且还积极参与炎症和免疫，而内在的调节机制尚不清楚。在这里，我们报告质子选择性离子通道 Hv1 在啮齿动物和人类周围感觉神经元中的表达，此前该通道被证明在哺乳动物中枢神经系统中的小胶质细胞中特异性表达。PN 或去极化刺激可上调神经元 Hv1，进而加重炎症和痛觉过敏。通过基因抑制或新发现的选择性抑制剂 YHV98-4 抑制神经元 Hv1 可减少炎症性疼痛中的细胞内碱化和 ROS 产生，减轻下游 SHP-1-pAKT 信号的失衡，并减少促炎趋化因子的释放，从而减轻痛觉过敏和吗啡引起的痛觉过敏和耐受。因此，我们的数据揭示了神经元 Hv1 作为一种新的镇痛策略和管理阿片类药物相关副作用的靶点。
