Volume 32, No 5, May 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 5, May 2022: 461-476

ORIGINAL ARTICLES

Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects

Qiansen Zhang^1,† , Yimin Ren^2,3,† , Yiqing Mo^1,† , Peipei Guo^1,† , Ping Liao^2,† , Yuncheng Luo^2,† , Jie Mu² , Zhuo Chen² , Yang Zhang¹ , Ya Li¹ , Linghui Yang² , Daqing Liao² , Jie Fu¹ , Juwen Shen¹ , Wei Huang⁴ , Xuewen Xu⁵ , Yanyan Guo^1,6 , Lianghe Mei⁶ , Yunxia Zuo² , Jin Liu² , Huaiyu Yang^1,* , Ruotian Jiang^2,*

¹Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China
²Laboratory 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
³Department of Anesthesiology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
⁴Department 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
⁵Department of Burn and Plastic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
⁶Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Suzhou, Jiangsu, China
^†These authors contributed equally: Qiansen Zhang, Yimin Ren, Yiqing Mo, Peipei Guo, Ping Liao, Yuncheng Luo
Correspondence: Huaiyu Yang(hyyang@bio.ecnu.edu.cn)Ruotian Jiang(ruotianjiang@scu.edu.cn)

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.

https://doi.org/10.1038/s41422-022-00616-y

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