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Increased HCN Channel Activity in the Gasserian Ganglion Contributes to Trigeminal Neuropathic Pain

  • Weihua Ding
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    The First Affiliated Hospital of Zhejiang University, Hangzhou, China
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  • Zerong You
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Shiqian Shen
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Jinsheng Yang
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Grewo Lim
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Jason T. Doheny
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Shengmei Zhu
    Affiliations
    The First Affiliated Hospital of Zhejiang University, Hangzhou, China
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  • Yi Zhang
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Lucy Chen
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Jianren Mao
    Correspondence
    Address reprint requests to Jianren Mao, MD, PhD, MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
    Affiliations
    MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
Published:January 21, 2018DOI:https://doi.org/10.1016/j.jpain.2018.01.003

      Highlights

      • Infraorbital nerve injury (dIoN-CCI) induced trigeminal neuropathic pain (TNP).
      • HCN1 and HCN2 were the major HCN isoforms in the gasserian ganglion (GG).
      • Inhibition of HCN channel activity in the GG ameliorated TNP.
      • HCN blocker ivabradine showed a prolonged analgesic effect.
      • HCN1 and HCN2 expression was increased in the GG after dIoN-CCI.

      Abstract

      Orofacial neuropathic pain caused by trigeminal nerve injury is a debilitating condition with limited therapeutic options. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability and are involved in the development and maintenance of chronic pain. However, the effect of HCN channel activity in the Gasserian ganglion on trigeminal neuropathic pain has not been examined. We evaluated nociceptive behaviors after microinjection of the HCN channel blockers ZD7288 or ivabradine into the Gasserian ganglion in rats with trigeminal nerve injury. Both blockers dose-dependently ameliorated evoked and spontaneous nociceptive behavior in rats with trigeminal neuropathic pain. Moreover, the clinically available HCN channel blocker ivabradine showed a prolonged antinociceptive effect. In the Gasserian ganglion, HCN1 and HCN2 are major HCN isoforms. After trigeminal nerve injury, the counts of HCN1 as well as HCN2 immuno-positive punctae were increased in the ipsilateral Gasserian ganglions. These results indicate that the increased HCN channel activity in the Gasserian ganglion directly contributes to neuropathic pain resulting from trigeminal nerve injury.

      Perspective

      Trigeminal nerve damage-induced orofacial pain is severe and more resistant to standard pharmacological treatment than other types of neuropathic pain. Our study suggests that targeting HCN channel activities in the Gasserian ganglion may provide an alternative treatment of trigeminal neuropathy including trigeminal neuralgia.

      Key words

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