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Endoplasmic Reticulum Stress Contributes to Nociception via Neuroinflammation in a Murine Bone Cancer Pain Model.

内质网应激通过神经炎症在小鼠骨癌痛模型中促进伤害性感受。

  • 影响因子:3.13
  • DOI:10.1097/ALN.0000000000003078
  • 作者列表:"Mao Y","Wang C","Tian X","Huang Y","Zhang Y","Wu H","Yang S","Xu K","Liu Y","Zhang W","Gu X","Ma Z
  • 发表时间:2020-02-01
Abstract

BACKGROUND:Prolonged endoplasmic reticulum stress has been identified in various diseases. Inflammatory mediators, which have been shown to induce endoplasmic reticulum stress in several studies, have been suggested to serve as the important modulators in pain development. In this study, the authors hypothesized that the endoplasmic reticulum stress triggered by inflammatory mediators contributed to pain development. METHODS:The authors used a male mouse model of bone cancer pain. The control mice were intrathecally injected with tumor necrosis factor-α (TNF-α) and lipopolysaccharide, the bone cancer pain mice were intrathecally injected with the endoplasmic reticulum stress inhibitors 4-PBA and GSK2606414. The nociceptive behaviors, endoplasmic reticulum stress markers, and inflammatory mediators were assessed. RESULTS:Increased expression of the p-RNA-dependent protein kinase-like endoplasmic reticulum kinase and p-eukaryotic initiation factor 2α were found in the spinal neurons during bone cancer pain, along with upregulation of inflammatory mediators (TNF-α, interleukin 1β, and interleukin 6). Intrathecal administration of TNF-α or lipopolysaccharide increased the expression of endoplasmic reticulum stress markers in control mice. Inhibition of endoplasmic reticulum stress by intrathecal administration of 4-PBA (baseline vs. 3 h: 0.34 ± 0.16 g vs. 1.65 ± 0.40 g in paw withdrawal mechanical threshold, 8.00 ± 1.20 times per 2 min vs. 0.88 ± 0.64 times per 2 min in number of spontaneous flinches, P < 0.001, n = 8) or GSK2606414 (baseline vs. 3 h: 0.37 ± 0.08 g vs. 1.38 ± 0.11 g in paw withdrawal mechanical threshold, 8.00 ± 0.93 times per 2 min vs. 3.25 ± 1.04 times per 2 min in number of spontaneous flinches, P < 0.001, n = 8) showed time- and dose-dependent antinociception. Meanwhile, decreased expression of inflammatory mediators (TNF-α, interleukin 1β, and interleukin 6), as well as decreased activation of astrocytes in the spinal cord, were found after 4-PBA or GSK2606414 treatment. CONCLUSIONS:Inhibition of inflammatory mediator-triggered endoplasmic reticulum stress in spinal neurons attenuates bone cancer pain via modulation of neuroinflammation, which suggests new approaches to pain relief.

摘要

背景: 在多种疾病中已发现长时间的内质网应激。炎症介质,在一些研究中被证明可以诱导内质网应激,被认为是疼痛发展的重要调节剂。在这项研究中,作者假设炎症介质触发的内质网应激有助于疼痛的发展。 方法: 作者采用雄性小鼠骨癌痛模型。对照组小鼠鞘内注射肿瘤坏死因子-α (TNF-α) 和脂多糖,骨癌痛小鼠鞘内注射内质网应激抑制剂 4-PBA和gsk2606414。评估伤害性行为、内质网应激标志物和炎症介质。 结果: 骨癌痛时脊髓神经元p-RNA依赖性蛋白激酶样内质网激酶和p-真核起始因子 2 α 的表达增加,随着炎症介质 (TNF-α 、白细胞介素 1 β 和白细胞介素 6) 的上调。鞘内给予TNF-α 或脂多糖增加了对照组小鼠内质网应激标志物的表达。通过鞘内给予 4-PBA抑制内质网应激 (基线vs. 3 h: 0.34 ± 0.16g vs.缩爪机械阈 1.65 ± 0.40g,8.00 ± 1.20 次/2 min vs. 0.88 ± 0.64 次/2 min自发退缩次数,P <0.001,n = 8)或GSK2606414 (基线vs. 3 h: 0.37 ± 0.08g vs.缩爪机械阈 1.38 ± 0.11g,8.00 ± 0.93 次/2 min vs. 3.25 ± 1.04 次/2 min自发退缩次数,P <0.001,n = 8) 显示时间和剂量依赖性抗伤害感受。同时,4-PBA或GSK2606414 治疗后发现炎症介质 (TNF-α 、白细胞介素 1 β 和白细胞介素 6) 表达减少,脊髓星形胶质细胞活化减少。 结论: 抑制炎症介质触发的脊髓神经元内质网应激通过调节神经炎症减轻骨癌痛,这提示了缓解疼痛的新方法。

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骨肿瘤方向

骨肿瘤是发生于骨骼或其附属组织的肿瘤。有良性,恶性之分,良性骨肿瘤易根治,预后良好,恶性骨肿瘤发展迅速,预后不佳,死亡率高。

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