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Nature 424, 778-783 (14 August 2003) | doi:10.1038/nature01786; Received 17 March 2003; Accepted 8 May 2003

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

Makoto Tsuda1,2, Yukari Shigemoto-Mogami1, Schuichi Koizumi3, Akito Mizokoshi4, Shinichi Kohsaka5, Michael W. Salter2 & Kazuhide Inoue1,4

  1. Division of Biosignaling, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan
  2. Programme in Brain and Behaviour, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
  3. Division of Pharmacology, National Institute of Health Sciences, 1-15-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan
  4. Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan
  5. Department of Neurochemistry, National Institute of Neuroscience, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan

Correspondence to: Kazuhide Inoue1,4 Email: inoue@nihs.go.jp

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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.

  1. Division of Biosignaling, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan
  2. Programme in Brain and Behaviour, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
  3. Division of Pharmacology, National Institute of Health Sciences, 1-15-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan
  4. Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan
  5. Department of Neurochemistry, National Institute of Neuroscience, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan

Correspondence to: Kazuhide Inoue1,4 Email: inoue@nihs.go.jp