title: Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain.
abstract: 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, P2X(4) receptors (P2X(4)R) are expressed de novo by activated microglia in the spinal cord. Using in vitro and in vivo models, we provide direct evidence that P2X(4)R 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 P2X(4)-deficient mice microglia in primary cultures. These results indicate that P2X(4)R contribute to chronic pain through a central inflammatory pathway. P2X(4)R might thus represent a potential therapeutic target to limit microglia-mediated inflammatory responses associated with brain injury and neurodegenerative disorders.
authors.affiliation: Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Montpellier, France.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Ulmann
authors.forename: Jon P
authors.initials: JP
authors.lastname: Hatcher
authors.forename: Jane P
authors.initials: JP
authors.lastname: Hughes
authors.forename: Séverine
authors.initials: S
authors.lastname: Chaumont
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Green
authors.forename: François
authors.initials: F
authors.lastname: Conquet
authors.forename: Gary N
authors.initials: GN
authors.lastname: Buell
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Reeve
authors.forename: Iain P
authors.initials: IP
authors.lastname: Chessell
authors.forename: Francois
authors.initials: F
authors.lastname: Rassendren
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D058848:Receptors, Purinergic P2X4; D013116:Spinal Cord / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C548227:P2rx4 protein, mouse; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4