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- Title
Phosphatidylinositol 3-Kinase Is a Key Mediator of Central Sensitization in Painful Inflammatory Conditions.
- Authors
Pezet, Sophie; Marchand, Fabien; D'Mello, Richard; Grist, John; Clark, Anna K.; Malcangio, Marzia; Dickenson, Anthony H.; Williams, Robert J.; McMahon, Stephen B.
- 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)AMPAreceptor 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.
- Subjects
PROTEIN kinases; CHRONIC pain; INFLAMMATION; PHOSPHORYLATION; METHYL aspartate; FORMALDEHYDE
- Publication
Journal of Neuroscience, 2008, Vol 28, Issue 16, p4261
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5392-07.2008