Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain.
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.
Ulmann
Lauriane
L
Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Montpellier, France.
Hatcher
Jon P
JP
Hughes
Jane P
JP
Chaumont
Séverine
S
Green
Paula J
PJ
Conquet
François
F
Buell
Gary N
GN
Reeve
Alison J
AJ
Chessell
Iain P
IP
Rassendren
Francois
F
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
D019208:Brain-Derived Neurotrophic Factor; C548227:P2rx4 protein, mouse; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4