Cdk5 contributes to inflammation-induced thermal hyperalgesia mediated by the p38 MAPK pathway in microglia
Cdk5 contributes to inflammation-induced thermal hyperalgesia mediated by the p38 MAPK pathway in microglia
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DOI：
10.1016/j.brainres.2015.01.056
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发表时间：
2015-09-04
期刊：
影响因子：
2.9
通讯作者：
Lu, Jin-Miao
中科院分区：
文献类型：
--
作者：
Fang-Hu;Zhang, Hong-Hai;Lu, Jin-Miao
背景：炎症诱导的细胞周期蛋白依赖性激酶5（Cdk 5）介导的热痛觉过敏的机制仍然知之甚少。在本研究中，我们研究了外周注射完全弗氏佐剂（CFA）引起的热痛觉过敏，以检测大鼠脊髓背角中通过p38丝裂原活化蛋白激酶（MAPK）的Cdk 5信号转导（p38 MAPK）信号通路，其已知在介导炎性疼痛中起作用。采用足底注射CFA的方法建立炎性痛模型，比较roscovitine和SB 203580对热痛敏的抑制作用。在CFA注射后第1天和第3天，我们使用免疫组织化学方法测量了Cdk 5、p35、OX-42和胶质细胞酸性蛋白（GFAP）在背角的定位，并且使用Western印迹分析测量了OX-42和磷酸化p38（p-p38）的蛋白水平。结果：CFA引起的热痛敏在注射后1d达到最大，5d后逐渐降低。在CFA注射后第1天，我们发现Cdk 5激活剂p35、小胶质细胞标记物OX-42和p-p38在相同的小胶质细胞和脊髓神经元中共定位;然而，我们没有看到p35和GFAP（活化星形胶质细胞的标记物）共定位。鞘内注射Cdk 5抑制剂roscovitine和p38抑制剂SB 203580可抑制CFA诱导的热痛觉过敏。此外，OX-42，p-p38，和TNF-α的表达显着增加，从第1天至第5天后CFA注射，并显着逆转roscovitine之间的1和3 day.Conclusions：Cdk 5，p38和TNF-α的上游调节，介导CFA诱导的热痛觉过敏。因此，通过药物阻断Cdk 5介导的p-p38的产生可能是减少炎性疼痛的新方法。这篇文章是题为SI：脊髓损伤的特刊的一部分。(C)2015作者由爱思唯尔公司出版。这是一篇开放获取的文章，获得了CC BY-NC-ND许可证（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Background: The mechanisms underlying cyclin-dependent kinase 5 (Cdk5)-mediated thermal hyperalgesia induced by inflammation remain poorly understood. In the present study, we examined thermal hyperalgesia provoked by peripheral injection of complete Freund's adjuvant (CFA) to test for Cdk5 signaling in the spinal dorsal horns of rats through the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway, which is known to function in mediating inflammatory pain.Methods: We induced the inflammatory pain model by plantar injection of CFA and compared the inhibitory effects of roscovitine and SB203580 on thermal hyperalgesia. We measured localization of Cdk5, p35, OX-42, and glial fibrillary acidic protein (GFAP) in the dorsal horn at 1 and 3 days after CFA injection using immunohistochemistry, and we measured protein levels of OX-42 and phosphorylated-p38 (p-p38) using Western blot analysis. Tumor necrosis factor-a (TNF-a) was measured by ELISA.Results: The maximum thermal hyperalgesia induced by CFA occurred at 1d following injection and decreased until 5 d. We found colocalization of the Cdk5 activator p35, the microglial marker OX-42 and p-p38 in the same microglial cells and neurons of the spinal cord at day 1 after CFA injection; however, we saw no colocalization of p35 and GFAP, a marker of activated astrocytes. The thermal hyperalgesia induced by CFA was inhibited by intrathecal administration of the Cdk5 inhibitor roscovitine and by the p38 inhibitor SB203580. Furthermore, the expression of OX-42, p-p38, and TNF-a was remarkably increased from days 1 to 5 post-CFA injection and were significantly reversed by roscovitine between 1 and 3 days.Conclusions: Cdk5, an upstream regulator of p38 and TNF-a, mediates CFA-induced thermal hyperalgesia. As such, pharmacological blocking of the generation of p-p38 mediated by Cdk5 may present a novel approach for diminishing inflammatory pain. This article is part of a Special Issue entitled SI: Spinal cord injury. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).