Up-regulation of tumor necrosis factor-alpha in spinal cord contributes to vincristine-induced mechanical allodynia in mice
Up-regulation of tumor necrosis factor-alpha in spinal cord contributes to vincristine-induced mechanical allodynia in mice
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DOI：
10.1016/j.neulet.2008.09.009
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发表时间：
2008-11-14
影响因子：
2.5
通讯作者：
Kishioka, Shiroh
中科院分区：
文献类型：
--
作者：
Kiguchi, Norikazu;Maeda, Takehiko;Kishioka, Shiroh
长春新碱（VCR）长期治疗会导致机械性异常性疼痛（不良反应）。我们以前报道过外周巨噬细胞来源的白细胞介素-6在VCR诱导的异常性疼痛中起关键作用。然而，胶质细胞活化和中枢致敏在VCR诱导的异常性疼痛中的作用尚不清楚。在这项研究中，我们专注于脊髓肿瘤坏死因子-α（TNF-α），并探讨TNF-α在VCR诱导的小鼠异常性疼痛中的作用。VCR（0.1 mg/kg，i.p.）每天一次给予小鼠7天。采用实时荧光定量PCR和免疫组织化学方法检测脊髓组织中TNF-α mRNA和蛋白的表达。在VCR处理的小鼠中，TNF-α mRNA逐渐增加，并在第7天显著上调。通过免疫组织化学测定，VCR给药第7天脊髓背角中的小胶质细胞和星形胶质细胞活化。TNF-α的免疫反应性共定位于一些活化的小胶质细胞和星形胶质细胞中。在行为分析中，在第0、3和6天鞘内注射TNF-α的中和抗体，在第4和7天显著减弱VCR诱导的机械性异常性疼痛。这些结果表明，VCR处理引起脊髓中胶质细胞的活化，这些细胞中上调的TNF-α可能在VCR诱导的机械性异常性疼痛中发挥重要作用。(c)2008爱思唯尔爱尔兰有限公司保留所有权利。
Chronic treatment with vincristine (VCR) causes mechanical allodynia as an adverse effect. We previously reported that peripheral macrophage-derived interleukin-6 played a critical role in VCR-induced allodynia. However, the involvement of glial cell activation and central sensitization in VCR-induced allodynia is still unclear. In this study, we focused on tumor necrosis factor-alpha (TNF-alpha) in spinal cord, and investigated the role of TNF-alpha in VCR-induced allodynia in mice. VCR (0.1 mg/kg, i.p.) was administered to mice once per day for 7 days. The expression of TNF-alpha mRNA and the protein in spinal cord was evaluated by quantitative real-time PCR and immunohistochemistry, respectively. In VCR-treated mice, TNF-alpha mRNA gradually increased and was significantly up-regulated on day 7. As measured by immunohistochemistry, microglia and astrocytes were activated in the spinal dorsal horn on day 7 of VCR administration. The immunoreactivity of TNF-alpha was co-localized in some of the activated microglia and astrocytes. In behavioral analysis, a neutralizing antibody of TNF-alpha, which was injected intrathecally on days 0, 3, and 6, significantly attenuated VCR-induced mechanical allodynia on days 4 and 7. These results suggest that VCR treatments elicited the activation of glial cells in spinal cord, and up-regulated TNF-alpha in these cells may play an important role in VCR-induced mechanical allodynia. (c) 2008 Elsevier Ireland Ltd. All rights reserved.