Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization.
Although the PI3K (phosphatidylinositol 3-kinase) pathway typically regulates cell growth and survival, increasing evidence indicates the involvement of this pathway in neural plasticity. It is unknown whether the PI3K pathway can mediate pain hypersensitivity. Intradermal injection of capsaicin and NGF produce heat hyperalgesia by activating their respective TRPV1 (transient receptor potential vanilloid receptor-1) and TrkA receptors on nociceptor sensory nerve terminals. We examined the activation of PI3K in primary sensory DRG neurons by these inflammatory agents and the contribution of PI3K activation to inflammatory pain. We further investigated the correlation between the PI3K and the ERK (extracellular signal-regulated protein kinase) pathway. Capsaicin and NGF induce phosphorylation of the PI3K downstream target AKT (protein kinase B), which is blocked by the PI3K inhibitors LY294002 and wortmannin, indicative of the activation of PI3K by both agents. ERK activation by capsaicin and NGF was also blocked by PI3K inhibitors. Similarly, intradermal capsaicin in rats activated PI3K and ERK in C-fiber DRG neurons and epidermal nerve fibers. Injection of PI3K or MEK (ERK kinase) inhibitors into the hindpaw attenuated capsaicin- and NGF-evoked heat hyperalgesia but did not change basal heat sensitivity. Furthermore, PI3K, but not ERK, inhibition blocked early induction of hyperalgesia. In acutely dissociated DRG neurons, the capsaicin-induced TRPV1 current was strikingly potentiated by NGF, and this potentiation was completely blocked by PI3K inhibitors and primarily suppressed by MEK inhibitors. Therefore, PI3K induces heat hyperalgesia, possibly by regulating TRPV1 activity, in an ERK-dependent manner. The PI3K pathway also appears to play a role that is distinct from ERK by regulating the early onset of inflammatory pain.
Zhuang
Zhi-Ye
ZY
Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Xu
Haoxing
H
Clapham
David E
DE
Ji
Ru-Rong
RR
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology; D009475:Neurons, Afferent / Q000201:enzymology*; D010147:Pain Measurement / Q000187:drug effects; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000294:innervation; D050916:TRPV Cation Channels; D000077191:Wortmannin
D000730:Androstadienes; D002211:Capsaicin; D002867:Chromones; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D007473:Ion Channels; D009025:Morpholines; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050916:TRPV Cation Channels; D000077191:Wortmannin; C493922:Trpv1 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494920:Akt1 protein, rat