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The Journal of Neuroscience, October 29, 2008, 28(44):11263-11268; doi:10.1523/JNEUROSCI.2308-08.2008

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Brief Communications
Up-Regulation of P2X₄ Receptors in Spinal Microglia after Peripheral Nerve Injury Mediates BDNF Release and Neuropathic Pain

Lauriane Ulmann,^1,2 Jon P. Hatcher,³ Jane P. Hughes,³ Séverine Chaumont,^1,2 Paula J. Green,³ François Conquet,⁴ Gary N. Buell,⁴ Alison J. Reeve,³ Iain P. Chessell,³ and Francois Rassendren^1,2

¹Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, and ²INSERM, U661, and Université Montpellier, 1, 2, 34094 Montpellier, France, ³Pain Research, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex CM19 5AW, United Kingdom, and ⁴GlaxoWellcome Biomedical Research Institute, Geneva 1228, Switzerland

Correspondence should be addressed to Francois Rassendren, Institut de Génomique Fonctionnelle, CNRS UMR5203, 141 rue de la Cardonille, 34094 Montpellier, France. Email: far{at}igh.cnrs.fr

ATP is a known mediator of inflammatory and neuropathic pain. However, the mechanisms by which specific purinergic receptors contribute to chronic pain states are still poorly characterized. Here, we demonstrate that in response to peripheral nerve injury, P2X₄ receptors (P2X₄R) are expressed de novo by activated microglia in the spinal cord. Using in vitro and in vivo models, we provide direct evidence that P2X₄R stimulation leads to the release of BDNF from activated microglia and, most likely phosphorylation of the NR1 subunit of NMDA receptors in dorsal horn neurons of the spinal cord. Consistent with these findings, P2X4-deficient mice lack mechanical hyperalgesia induced by peripheral nerve injury and display impaired BDNF signaling in the spinal cord. Furthermore, ATP stimulation is unable to stimulate BDNF release from P2X₄-deficient mice microglia in primary cultures. These results indicate that P2X₄R contribute to chronic pain through a central inflammatory pathway. P2X₄R might thus represent a potential therapeutic target to limit microglia-mediated inflammatory responses associated with brain injury and neurodegenerative disorders.

Key words: P2X₄; microglia; BDNF; pain; knock-out; mice

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Received May 21, 2008; revised Sept. 9, 2008; accepted Sept. 22, 2008.

Correspondence should be addressed to Francois Rassendren, Institut de Génomique Fonctionnelle, CNRS UMR5203, 141 rue de la Cardonille, 34094 Montpellier, France. Email: far{at}igh.cnrs.fr

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