Signaling of ATP receptors in glia-neuron interaction and pain.
ATP causes the activation of p38 or ERK1/2, mitogen activated protein kinases (MAPKs) resulting in the release of tumor necrosis factor-alpha (TNF) and Interleukin-6 (IL-6) from microglia. We examined the effect of TNF and IL-6 on the protection from PC12 cell death by serum deprivation. When PC12 cells were incubated with serum-free medium for 32 hr, their viability decreased to 30 %. IL-6 alone slightly protected the death of PC12 cells, whereas TNF alone did not show any protective effect. In the meanwhile, when PC12 cells were pretreated with TNF for 6 hr and then incubated with IL-6 under the condition of serum-free, the viability of PC12 cells dramatically increased. TNF induced an increase of IL-6 receptor (IL-6R) expression in PC12 cells at 4-6 hr. These data suggested that 6 hr pretreatment with TNF increased IL-6R expression in PC12 cells, leading to an enhancement of IL-6-induced neuroprotective action.To elucidate the role of p38 in pathological pain, we investigated whether p38 is activated in the spinal cord of the neuropathic pain model. In the rats displaying a marked allodynia, the level of phospho-p38 was increased in the microglia of injury side in the dorsal horn. Intraspinal administration of p38 inhibitor suppressed the allodynia. These results demonstrate that neuropathic pain hypersensitivity depends upon the activation of p38 signaling pathway in microglia in the dorsal horn following peripheral nerve injury.
Inoue
Kazuhide
K
Division of Biosignaling, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, 158-8501, Tokyo, Japan. inoue@nihs.go.jp
Koizumi
Schuichi
S
Tsuda
Makoto
M
Shigemoto-Mogami
Yukari
Y
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016158:Genes, p53 / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D016716:PC12 Cells; D010146:Pain / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000473:pathology; D020671:Posterior Horn Cells / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018048:Receptors, Purinergic P2; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases