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Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain

Author

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  • Takahiro Masuda

    (Graduate School of Pharmaceutical Sciences, Kyushu University
    Graduate School of Pharmaceutical Sciences, Kyushu University
    Institute of Neuropathology, University of Freiburg
    JST, CREST)

  • Yui Ozono

    (Graduate School of Pharmaceutical Sciences, Kyushu University)

  • Satsuki Mikuriya

    (Graduate School of Pharmaceutical Sciences, Kyushu University)

  • Yuta Kohro

    (Graduate School of Pharmaceutical Sciences, Kyushu University
    Graduate School of Pharmaceutical Sciences, Kyushu University)

  • Hidetoshi Tozaki-Saitoh

    (Graduate School of Pharmaceutical Sciences, Kyushu University
    Graduate School of Pharmaceutical Sciences, Kyushu University
    JST, CREST)

  • Ken Iwatsuki

    (Institute for Innovation, Ajinomoto Co., Inc.
    Tokyo University of Agriculture)

  • Hisayuki Uneyama

    (Institute for Innovation, Ajinomoto Co., Inc.)

  • Reiko Ichikawa

    (Institute for Innovation, Ajinomoto Co., Inc.)

  • Michael W. Salter

    (Program in Neurosciences & Mental Health, Hospital for Sick Children
    University of Toronto)

  • Makoto Tsuda

    (Graduate School of Pharmaceutical Sciences, Kyushu University
    Graduate School of Pharmaceutical Sciences, Kyushu University)

  • Kazuhide Inoue

    (Graduate School of Pharmaceutical Sciences, Kyushu University
    JST, CREST)

Abstract

Activation of purinergic receptors in the spinal cord by extracellular ATP is essential for neuropathic hypersensitivity after peripheral nerve injury (PNI). However, the cell type responsible for releasing ATP within the spinal cord after PNI is unknown. Here we show that PNI increases expression of vesicular nucleotide transporter (VNUT) in the spinal cord. Extracellular ATP content ([ATP]e) within the spinal cord was increased after PNI, and this increase was suppressed by exocytotic inhibitors. Mice lacking VNUT did not show PNI-induced increase in [ATP]e and had attenuated hypersensitivity. These phenotypes were recapitulated in mice with specific deletion of VNUT in spinal dorsal horn (SDH) neurons, but not in mice lacking VNUT in primary sensory neurons, microglia or astrocytes. Conversely, ectopic VNUT expression in SDH neurons of VNUT-deficient mice restored PNI-induced increase in [ATP]e and pain. Thus, VNUT is necessary for exocytotic ATP release from SDH neurons which contributes to neuropathic pain.

Suggested Citation

  • Takahiro Masuda & Yui Ozono & Satsuki Mikuriya & Yuta Kohro & Hidetoshi Tozaki-Saitoh & Ken Iwatsuki & Hisayuki Uneyama & Reiko Ichikawa & Michael W. Salter & Makoto Tsuda & Kazuhide Inoue, 2016. "Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain," Nature Communications, Nature, vol. 7(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12529
    DOI: 10.1038/ncomms12529
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