Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury.
Neuropathic pain is an expression of pathological operation of the nervous system, which commonly results from nerve injury and is characterized by pain hypersensitivity to innocuous stimuli, a phenomenon known as tactile allodynia. The mechanisms by which nerve injury creates tactile allodynia have remained largely unknown. We report that the development of tactile allodynia following nerve injury requires activation of p38 mitogen-activated protein kinase (p38MAPK), a member of the MAPK family, in spinal microglia. We found that immunofluorescence and protein levels of the dually phosphorylated active form of p38MAPK (phospho-p38MAPK) were increased in the dorsal horn ipsilateral to spinal nerve injury. Interestingly, the phospho-p38MAPK immunofluorescence in the dorsal horn was found exclusively in microglia, but not in neurons or astrocytes. The level of phospho-p38MAPK immunofluorescence in individual microglial cells was much higher in the hyperactive phenotype in the ipsilateral dorsal horn than the resting one in the contralateral side. Intrathecal administration of the p38MAPK inhibitor, 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), suppresses development of the nerve injury-induced tactile allodynia. Taken together, our results demonstrate that nerve injury-induced pain hypersensitivity depends on activation of the p38MAPK signaling pathway in hyperactive microglia in the dorsal horn following peripheral nerve injury.
Tsuda
Makoto
M
Division of Biosignaling, National Institute of Health Sciences, Tokyo, Japan.
Mizokoshi
Akito
A
Shigemoto-Mogami
Yukari
Y
Koizumi
Schuichi
S
Inoue
Kazuhide
K
D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D017628:Microglia / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010146:Pain / Q000201:enzymology*; D010523:Peripheral Nervous System Diseases / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000201:enzymology*; D013127:Spinal Nerves / Q000201:enzymology / Q000293:injuries; D048051:p38 Mitogen-Activated Protein Kinases
D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases