title: Downregulation of ClC-3 in dorsal root ganglia neurons contributes to mechanical hypersensitivity following peripheral nerve injury.
abstract: ClC-3 chloride channel/antiporter has been demonstrated to play an important role in synaptic transmission in central nervous system. However, its expression and function in sensory neurons is poorly understood. In present work, we found that ClC-3 is expressed at high levels in dorsal root ganglia (DRG). Co-immunofluorescent data showed that ClC-3 is mainly distributed in A- and C-type nociceptive neurons. ClC-3 expression in DRG is decreased in the spared nerve injury (SNI) model of neuropathic pain. Knockdown of local ClC-3 in DRG neurons with siRNA increased mechanical sensitivity in naïve rats, while overexpression of ClC-3 reversed the hypersensitivity to mechanical stimuli after peripheral nerve injury. In addition, genetic deletion of ClC-3 enhances mouse mechanical sensitivity but did not affect thermal and cold threshold. Restoration of ClC-3 expression in ClC-3 deficient mice reversed the mechanical sensitivity. Mechanistically, loss of ClC-3 enhanced mechanical sensitivity through increasing the excitability of DRG neurons. These data indicate that ClC-3 is an endogenous inhibitor of neuropathic pain development. Downregulation of ClC-3 by peripheral nerve injury is critical for mechanical hypersensitivity. Our findings suggest that ClC-3 is a novel therapeutic target for treating neuropathic pain.
authors.affiliation: Department of Physiology, Pain Research Center, Zhongshan School of Medicine, China. Electronic address: pangruip@mail.sysu.edu.cn.
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Pang
authors.affiliation: Department of Physiology, Pain Research Center, Zhongshan School of Medicine, China.
authors.forename: Man-Xiu
authors.initials: MX
authors.lastname: Xie
authors.affiliation: Department of Physiology, Pain Research Center, Zhongshan School of Medicine, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Physiology, Pain Research Center, Zhongshan School of Medicine, China.
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Shen
authors.affiliation: Department of Rehabilitation Medicine, The Third Affiliated Hospital, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, China.
authors.forename: Ying-Xue
authors.initials: YX
authors.lastname: Su
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, China.
authors.forename: Si-Jia
authors.initials: SJ
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Pain Research Center, Zhongshan School of Medicine, China.
authors.forename: He-Quan
authors.initials: HQ
authors.lastname: Zhu
authors.affiliation: Department of Physiology, Pain Research Center, Zhongshan School of Medicine, China.
authors.forename: Xu-Hong
authors.initials: XH
authors.lastname: Wei
authors.affiliation: Department of Physiology, Pain Research Center, Zhongshan School of Medicine, China.
authors.forename: Yong-Yong
authors.initials: YY
authors.lastname: Li
authors.affiliation: National Key Laboratory of Biomolecules, CAS-UT Joint Lab of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zhi-Hai
authors.initials: ZH
authors.lastname: Qin
authors.affiliation: Department of Physiology, Pain Research Center, Zhongshan School of Medicine, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China. Electronic address: liuxg@mail.sysu.edu.cn.
authors.forename: Xian-Guo
authors.initials: XG
authors.lastname: Liu
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010147:Pain Measurement / Q000379:methods; D059348:Peripheral Nerve Injuries / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018118:Chloride Channels; C115376:ClC-3 channel
keywords: ClC-3; Dorsal root ganglia; Mechanical hypersensitivity; Neuropathic pain; Peripheral nerve injury