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 (0.1mg/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.

译文

长春新碱 (VCR) 的慢性治疗会导致机械性异常性疼痛,这是一种不良反应。我们先前报道了外周巨噬细胞衍生的interleukin-6在VCR诱导的异常性疼痛中起关键作用。然而,神经胶质细胞活化和中枢敏化参与VCR诱导的异常性疼痛仍不清楚。在这项研究中,我们重点研究了脊髓中的肿瘤坏死因子-α (TNF-α),并研究了TNF-α 在VCR诱导的小鼠异常性疼痛中的作用。每天给小鼠一次VCR (0.1 mg/kg,i.p.),持续7天。通过实时定量PCR和免疫组织化学分别评估了TNF-α mRNA和蛋白在脊髓中的表达。在VCR处理的小鼠中,TNF-α mRNA逐渐增加,并在第7天显着上调。通过免疫组织化学测量,在VCR给药的第7天,小胶质细胞和星形胶质细胞在脊髓背角被激活。TNF-α 的免疫反应性共定位在某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天鞘内注射的TNF-α 中和抗体在第4天和第7天显着减轻了VCR诱导的机械性异常性疼痛。这些结果表明,VCR治疗可引起脊髓中神经胶质细胞的激活,而这些细胞中TNF-α 的上调可能在VCR诱导的机械性异常性疼痛中起重要作用。

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