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The Journal of Neuroscience, April 16, 2008, 28(16):4261-4270; doi:10.1523/JNEUROSCI.5392-07.2008

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Development/Plasticity/Repair
Phosphatidylinositol 3-Kinase Is a Key Mediator of Central Sensitization in Painful Inflammatory Conditions

Sophie Pezet,¹ Fabien Marchand,¹ Richard D'Mello,³ John Grist,¹ Anna K. Clark,¹ Marzia Malcangio,¹ Anthony H. Dickenson,³ Robert J. Williams,² and Stephen B. McMahon¹

¹Neurorestoration Group and ²Receptor and Signalling Group, Wolfson Center for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom, and ³Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom

Correspondence should be addressed to Dr. Sophie Pezet, Laboratoire de Neurobiologie, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7637, Ecole Supérieure de Physique et de Chimie Industrielles, 10 rue Vauquelin, 75005 Paris, France. Email: sophie.pezet{at}espci.fr

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.

Key words: phosphorylation; ERK; GluR1; CaMKII; NMDA; formalin

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Received Dec. 6, 2007; revised Feb. 15, 2008; accepted March 12, 2008.

Correspondence should be addressed to Dr. Sophie Pezet, Laboratoire de Neurobiologie, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7637, Ecole Supérieure de Physique et de Chimie Industrielles, 10 rue Vauquelin, 75005 Paris, France. Email: sophie.pezet{at}espci.fr

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				M. C. Opazo, A. Gianini, F. Pancetti, G. Azkcona, L. Alarcon, R. Lizana, V. Noches, P. A. Gonzalez, M. Porto, S. Mora, et al. Maternal Hypothyroxinemia Impairs Spatial Learning and Synaptic Nature and Function in the Offspring Endocrinology, October 1, 2008; 149(10): 5097 - 5106. [Abstract] [Full Text] [PDF]

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