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.

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;Department of Anesthesiology,the Affiliated Hospital of Guizhou Medical University,Guiyang,Guizhou,China;Department of Integrated Traditional Chinese and Western Medicine,Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre,West China Hospital,Sichuan University,Chengdu,Sichuan,China;Department of Burn and Plastic Surgery,West China Hospital of Sichuan University,Chengdu,Sichuan,China;Suzhou Institute of Drug Innovation,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Suzhou,Jiangsu,China

[1]Qiansen Zhang;Yimin Ren;Yiqing Mo;Peipei Guo;Ping Liao;Yuncheng Luo;Jie Mu;Zhuo Chen;Yang Zhang;Ya Li;Linghui Yang;Daqing Liao;Jie Fu;Juwen Shen;Wei Huang;Xuewen Xu;Yanyan Guo;Lianghe Mei;Yunxia Zuo;Jin Liu;Huaiyu Yang;Ruotian Jiang-.Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects)[J].细胞研究（英文版）,2022(05):461-476

YHV98

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