Phosphatidylinositol 3-kinase is a key mediator of central sensitization in painful inflammatory conditions

Sophie Pezet, Fabien Marchand, Richard D'Mello, John Grist, Anna K Clark, Marzia Malcangio, Anthony H Dickenson, Robert J Williams, Stephen B McMahon

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Here, we show that phosphatidylinositol 3-kinase (PI3K) is a key player in the establishment of central sensitization, the spinal cord phenomenon associated with persistent afferent inputs and contributing to chronic pain states. We demonstrated electrophysiologically that PI3K is required for the full expression of spinal neuronal wind-up. In an inflammatory pain model, intrathecal administration of LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], a potent PI3K inhibitor, dose-dependently inhibited pain-related behavior. This effect was correlated with a reduction of the phosphorylation of ERK (extracellular signal-regulated kinase) and CaMKII (calcium/calmodulin-dependent protein kinase II). In addition, we observed a significant decrease in the phosphorylation of the NMDA receptor subunit NR2B, decreased translocation to the plasma membrane of the GluR1 (glutamate receptor 1) AMPA receptor subunit in the spinal cord, and a reduction of evoked neuronal activity as measured using c-Fos immunohistochemistry. Our study suggests that PI3K is a major factor in the expression of central sensitization after noxious inflammatory stimuli.
Original languageEnglish
Pages (from-to)4261-4270
Number of pages10
JournalThe Journal of Neuroscience: The Official Journal of the Society for Neuroscience
Volume28
Issue number16
DOIs
Publication statusPublished - 16 Apr 2008

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