Endoplasmic Reticulum Stress Contributes to Nociception via Neuroinflammation in a Murine Bone Cancer Pain Model
Endoplasmic Reticulum Stress Contributes to Nociception via Neuroinflammation in a Murine Bone Cancer Pain Model
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在小鼠骨癌疼痛模型中，内质网应激通过神经炎症导致伤害感受
DOI：
10.1097/aln.0000000000003078
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发表时间：
2020-02-01
期刊：
影响因子：
8.8
通讯作者：
Ma, Zhengliang
中科院分区：
文献类型：
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作者：
Mao, Yanting;Wang, Chenchen;Ma, Zhengliang
背景：长时间的内质网应激在多种疾病中被发现。炎症介质在一些研究中被证明可以诱导内质网应激，被认为是疼痛发生过程中的重要调节因子。在这项研究中，作者假设由炎症介质引发的内质网应激促进了疼痛的发展。方法：作者使用了一种骨癌痛的雄性小鼠模型。对照组小鼠鞘内注射肿瘤坏死因子-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中p-RNA依赖的蛋白激酶样内质网蛋白激酶和p-真核细胞起始因子2α表达增加，同时炎性介质(肿瘤坏死因子-α、白介素1β和白介素6)表达上调。鞘内注射肿瘤坏死因子-α或脂多糖可增加对照组小鼠内质网应激标志物的表达。鞘内注射4-PBA可抑制内质网应激(基础值与3h分别为0.34+/-0.16g与1.65+/-0.40g，自发收缩次数分别为8.00+/-1.20次/2min与0.88+/-0.64次/2min，P<；0.001，n=8)或GSK2606414(基线vs.3h：0.37+/-0.08g vs.1.38+/-0.11g，自发缩爪次数：8.00+/-0.93次/2min vs.3.25+/-1.04次/2min，P<；0.001，n=8)表现出时间和剂量依赖性的抗伤害效应。同时，经4-PBA或GSK2606414治疗后，炎性介质(肿瘤坏死因子-α、白介素1-β和白介素6)的表达减少，脊髓星形胶质细胞的激活也减少。结论：抑制炎症介质触发的脊髓神经元内质网应激可通过调节神经炎症来减轻骨癌疼痛，这为缓解疼痛提供了新的方法。
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-alpha (TNF-alpha) 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 2 alpha were found in the spinal neurons during bone cancer pain, along with upregulation of inflammatory mediators (TNF-alpha, interleukin 1 beta, and interleukin 6). Intrathecal administration of TNF-alpha 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-alpha, interleukin 1 beta, 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.