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P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury

Author

Listed:
  • Makoto Tsuda

    (National Institute of Health Sciences
    The Hospital for Sick Children)

  • Yukari Shigemoto-Mogami

    (National Institute of Health Sciences)

  • Schuichi Koizumi

    (National Institute of Health Sciences)

  • Akito Mizokoshi

    (Kyushu University)

  • Shinichi Kohsaka

    (National Institute of Neuroscience)

  • Michael W. Salter

    (The Hospital for Sick Children)

  • Kazuhide Inoue

    (National Institute of Health Sciences
    Kyushu University)

Abstract

Pain after nerve damage is an expression of pathological operation of the nervous system1,2, one hallmark of which is tactile allodynia—pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X4 receptors (P2X4Rs)3,4,5,6,7, a subtype of ionotropic ATP receptor8, reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X4R expression increased strikingly in the ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4Rs and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4Rs had been induced and stimulated, produced tactile allodynia in naive rats. Taken together, our results demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.

Suggested Citation

  • Makoto Tsuda & Yukari Shigemoto-Mogami & Schuichi Koizumi & Akito Mizokoshi & Shinichi Kohsaka & Michael W. Salter & Kazuhide Inoue, 2003. "P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury," Nature, Nature, vol. 424(6950), pages 778-783, August.
  • Handle: RePEc:nat:nature:v:424:y:2003:i:6950:d:10.1038_nature01786
    DOI: 10.1038/nature01786
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    Cited by:

    1. N Ruiz-Suarez & SFM Bhatti & M Hermans & CB Silva & M Hesta, 2021. "Food hypersensitivity and feline hyperaesthesia syndrome (FHS): A case report," Veterinární medicína, Czech Academy of Agricultural Sciences, vol. 66(8), pages 363-367.
    2. Shannon Tansley & Sonali Uttam & Alba Ureña Guzmán & Moein Yaqubi & Alain Pacis & Marc Parisien & Haley Deamond & Calvin Wong & Oded Rabau & Nicole Brown & Lisbet Haglund & Jean Ouellet & Carlo Santag, 2022. "Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Cheng Shen & Yuqing Zhang & Wenwen Cui & Yimeng Zhao & Danqi Sheng & Xinyu Teng & Miaoqing Shao & Muneyoshi Ichikawa & Jin Wang & Motoyuki Hattori, 2023. "Structural insights into the allosteric inhibition of P2X4 receptors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Yiyi Ma & Eric B. Dammer & Daniel Felsky & Duc M. Duong & Hans-Ulrich Klein & Charles C. White & Maotian Zhou & Benjamin A. Logsdon & Cristin McCabe & Jishu Xu & Minghui Wang & Thomas S. Wingo & James, 2021. "Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    5. George Sideris-Lampretsas & Silvia Oggero & Lynda Zeboudj & Rita Silva & Archana Bajpai & Gopuraja Dharmalingam & David A. Collier & Marzia Malcangio, 2023. "Galectin-3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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