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Calcium Channel α2δ1 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling

  • Author Footnotes
    1 These authors contributed equally to this work.
    Wen-Qiang Cui
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Yu-Xia Chu
    Correspondence
    Address reprint requests to Yu-Xia Chu, PhD, Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Road, Xuhui District, Shanghai 200032, P.R. China.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
    Search for articles by this author
  • Fei Xu
    Affiliations
    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China

    Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, P.R. China
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  • Teng Chen
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
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  • Lu Gao
    Affiliations
    Department of Anatomy, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China
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  • Yi Feng
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
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  • Xue-Ming Hu
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
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  • Wei Yang
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
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  • Li-Xia Du
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
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  • Wen-Wen Zhang
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
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  • Qi-Liang Mao-Ying
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
    Search for articles by this author
  • Wen-Li Mi
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
    Search for articles by this author
  • Yan-Qing Wang
    Affiliations
    Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China

    Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, P.R. China

    Institutes of Integrative Medicine, Fudan University, Shanghai, P.R. China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
Published:September 05, 2019DOI:https://doi.org/10.1016/j.jpain.2019.08.012

      Highlights

      • Infraorbital nerve injury induces primary and secondary orofacial hyperalgesia.
      • Cavα2δ1 contributes to the development of secondary orofacial hyperalgesia.
      • Cavα2δ1 mediates secondary orofacial hyperalgesia through PKC-TRPA1/GJ pathway.

      Abstract

      Orofacial pain is characterized by its easy spread to adjacent areas, thus presenting with primary hyperalgesia (hypersensitivity at the site of injury) and secondary hyperalgesia (extraterritorial hypersensitivity outside the injured zone). However, the mechanisms behind the secondary hyperalgesia are poorly understood. In the present study, we used a mouse model of partial transection of the infraorbital nerve (pT-ION) to study whether calcium channel subunit α2δ1 (Cavα2δ1) and its downstream signaling contributes to the development of secondary hyperalgesia in the orofacial area. pT-ION caused primary (V2 skin) and secondary (V3 skin) hyperalgesia, which was reversed by the Cavα2δ1 antagonist gabapentin and by the expression of Cavα2δ1-targeting interfering RNA in trigeminal ganglion (TG)-V3 neurons. pT-ION induced increased expression of PKC and TRPA1, which was reversed by Cavα2δ1-targeting interfering RNA, and PKC inhibition reversed the upregulation of TRPA1 and gap junction (GJ) proteins induced by pT-ION. Cavα2δ1 overexpression in TG-V2 neurons induced the upregulation of PKC, TRPA1, and the GJ proteins in the TG and trigeminal subnucleus caudalis and induced hypersensitivity in the V3 skin area, which was reversed by TRPA1, GJ, or PKC blockade. Thus, we conclude that Cavα2δ1 contributes to the development of secondary hyperalgesia through its downstream PKC-TRPA1/GJ signaling pathways.

      Perspective

      This study demonstrates that the activation of Cavα2δ1 and the downstream PKC-TRPA1/GJ signaling pathway contributes greatly to trigeminal nerve injury-induced secondary mechanical and cold hyperalgesia. This suggests that inhibitors of Cavα2δ1, TRPA1, or GJs might be effective treatments for nerve injury-induced spreading of orofacial pain.

      Graphical Abstract

      Keywords

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