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

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.

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Figure 1: Spinal administration of TNP-ATP but not PPADS reverses tactile allodynia caused by injury to the L5 spinal nerve.
Figure 2: Marked upregulation of P2X4R level in the spinal dorsal horn after injury to the L5 nerve.
Figure 3: P2X4R is induced in hyperactive microglia but not in neurons or astrocytes.
Figure 4: P2X4R antisense ODN suppresses the development of tactile allodynia caused by injury to the L5 spinal nerve.
Figure 5: Spinal administration of ATP-stimulated microglia in normal rats produces tactile allodynia that depends on P2X4Rs.

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Acknowledgements

We thank J. Hicks for corrections to the manuscript. This work was supported by a Domestic Research Fellowship from the Japan Science and Technology Corporation, by a grant from the Uehara Memorial Foundation, partly by a grant from the Organization for Pharmaceutical Safety and Research, by a grant-in-aid for the scientific research from the Ministry of Education, Science, Sports, and Culture of Japan, and by a grant from the Japan Health Sciences Foundation. M.T. is supported by the Research Training Centre of the Hospital for Sick Children Research Institute. M.W.S. is an Investigator of the Canadian Institutes of Health Research.

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Correspondence to Kazuhide Inoue.

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Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003). https://doi.org/10.1038/nature01786

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