Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury
Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury
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作者：
Tsuda, M;Mizokoshi, A;Inoue, K
神经性疼痛是神经系统病理性运作的表现，通常由神经损伤引起，其特征是对无害刺激的疼痛过敏，这种现象称为触觉异常性疼痛。神经损伤引起触觉异常性疼痛的机制在很大程度上仍不清楚。我们报道神经损伤后触觉异常性疼痛的发生需要脊髓小胶质细胞中 p38 丝裂原激活蛋白激酶 (p38MAPK) 的激活，p38MAPK 是 MAPK 家族的成员。我们发现，在脊髓神经损伤同侧的背角中，p38MAPK（磷酸化-p38MAPK）的双重磷酸化活性形式的免疫荧光和蛋白质水平增加。有趣的是，背角中的磷酸化 p38MAPK 免疫荧光仅在小胶质细胞中发现，但在神经元或星形胶质细胞中没有发现。同侧背角过度活跃表型的单个小胶质细胞的磷酸化 p38MAPK 免疫荧光水平远高于对侧休息的小胶质细胞。鞘内注射 p38MAPK 抑制剂 4-(4-氟苯基)2-(4-甲基磺酰基苯基)-5-(4-吡啶基)-1H-咪唑 (SB203580) 可抑制神经损伤引起的触觉异常性疼痛的发生。综上所述，我们的结果表明，神经损伤引起的疼痛超敏反应取决于周围神经损伤后背角过度活跃的小胶质细胞中 p38MAPK 信号通路的激活。 (C) 2003 Wiley-Liss, Inc.
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. (C) 2003 Wiley-Liss, Inc.