Abstract
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.
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Acknowledgements
We thank Prof. Jun-Li Cao (Xuzhou Medical University, China), Prof. Xia Zhang (University of Ottawa, Canada) for helpful discussion on the manuscript, J. Zhang, Z. Yang, and L. Bai (Histology and Imaging platform, Core Facility of West China Hospital) for assistance with acquiring some ISH images; Li Li, Fei Chen and Chunjuan Bao (Institute of Clinical Pathology, West China Hospital) for processing histological staining. Yuandong Liu and Prof. Yang Tian (East China Normal University) for assistance in pH imaging. We thank the support of ECNU Multifunctional Platform for Innovation (001 and 011). This work was equally funded by the National Natural Science Foundation of China (32071003 to R.J.) and the Ministry of Science and Technology of China (2018ZX09711002 to Q.Z.), partially funded by the National Natural Science Foundation of China (81873808 to Y.Z, 31600832 to R.J., 31800699 to Q.Z.), the Fundamental Research Funds for the Central Universities (to H.Y. and 2018SCUH0086 to R.J.), the “XingFuZhiHua” funding of ECNU (44300-19311-542500/006 to H.Y.), the Department of Science and Technology of Sichuan Province (2020ZYD006 to R.J.) and the 1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University (ZYJC21034 to R.J.).
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Q.Z. performed drug design and computations. Y.R. performed electrophysiology in DRG, DRG microinjection, behavioral tests, cytokine and chemokine measurement, ISH, IHC, and ROS imaging. Y.M performed mouse genetics on Hvcn1−/− mice, pharmacokinetics study, behavioral tests, skin histopathological study, and ROS imaging. P.G. performed electrophysiology in HEK293 cells. P.L. performed ISH, IHC, pH and ROS imaging. Y.Luo performed ISH, IHC, ROS imaging, ELISA and behavioral tests. J.M. performed IHC and pH imaging. Z.C. and J.F. performed electrophysiology in HEK293 cells. Y.Zhang performed IHC imaging. Y.Li performed ROS imaging. L.Y. and D.L. performed some behavioral tests. J.S. performed drug design. W.H. and X.X. acquired and prepared human skin tissues. Y.G. performed behavioral tests, and ROS imaging. L.M. synthetized YHV98-4. Y.Zuo and J.L. oversaw some behavioral tests. H.Y. and R.J. initiated, supervised the project, analyzed the experiments, and wrote the manuscript with input from all coauthors.
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H.Y., R.J., and Q.Z. are inventors on a patent application (202011283354.3) submitted by East China Normal University, West China Hospital of Sichuan University and Shaoxing ZeroIn Biomedicines Co. Ltd. that cover the potential usage of YHV98-1, YHV98-4 and their derivatives.
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Zhang, Q., Ren, Y., Mo, Y. et al. Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects. Cell Res 32, 461–476 (2022). https://doi.org/10.1038/s41422-022-00616-y
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DOI: https://doi.org/10.1038/s41422-022-00616-y
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