Phosphatidylinositol 3-kinase is a key mediator of central sensitization in painful inflammatory conditions.
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.
Pezet
Sophie
S
Neurorestoration Group, Wolfson Center for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom. sophie.pezet@espci.fr
Marchand
Fabien
F
D'Mello
Richard
R
Grist
John
J
Clark
Anna K
AK
Malcangio
Marzia
M
Dickenson
Anthony H
AH
Williams
Robert J
RJ
McMahon
Stephen B
SB
D000818:Animals; D002867:Chromones / Q000494:pharmacology; D005557:Formaldehyde / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology
D002867:Chromones; D005557:Formaldehyde; D018836:Inflammation Mediators; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one