Despite broad clinical implications, the mechanisms linking inflammation and pain remain incompletely understood. Using human experimental endotoxemia as a translational model of systemic inflammation, we aimed to elucidate putative vulnerability factors of inflammation-induced musculoskeletal hyperalgesia. We pooled data from three published randomized controlled trials, resulting in a sample of N=98 healthy volunteers who received either low-dose endotoxin (lipopolysaccharide) or vehicle (saline) intravenously. As measure of musculoskeletal pain sensitivity, pressure pain thresholds (PPTs) were assessed at baseline and 3h post injection with a handheld algometer for the low back (erector spinae muscle), calf (gastrocnemius muscle), and shoulder region (deltoid muscle). Implementing multiple regression models, we tested the contribution of putative vulnerability factors on musculoskeletal hyperalgesia during systemic inflammation, including acute changes in pro-inflammatory cytokines, state anxiety and mood, as well as pre-existing symptoms of anxiety and depression. Endotoxin application led to significant increases in plasma cytokines, state anxiety, and negative mood, and significantly decreased PPTs for all muscle groups. Regression models revealed that greater M. erector spinae PPT changes were predicted by higher HADS-anxiety scores. Higher TNF-α concentration emerged as predictor for M. gastrocnemius PPT changes, and more pronounced TNF-α increase and higher HADS-anxiety were predictive for M. deltoideus PPTs. HADS scores emerged as predictor for a mean PPT score (computed across all body sites). Together, our results indicate that musculoskeletal hyperalgesia during systemic inflammation is related to pro-inflammatory cytokines, specifically TNF-α. Importantly, subclinical anxiety symptoms (even though in a low and normal range in this cohort of healthy volunteers) may contribute to inflammation-induced hyperalgesia, making individuals more vulnerable to the detrimental effects of systemic inflammation.

中文翻译：

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阐明炎症引起的痛觉过敏的脆弱性：实验性内毒素血症期间肌肉骨骼疼痛敏感性增加的预测因素

尽管具有广泛的临床意义，但仍不完全了解将炎症和疼痛联系起来的机制。使用人类实验性内毒素血症作为全身炎症的转化模型，我们旨在阐明炎症诱导的肌肉骨骼痛觉过敏的假定脆弱因素。我们汇总了三项已发表的随机对照试验的数据，得出了 N=98 名健康志愿者的样本，这些志愿者接受了低剂量内毒素（脂多糖）或静脉注射赋形剂（盐水）。作为肌肉骨骼疼痛敏感性的衡量标准，在基线和注射后 3 小时，使用手持式测痛仪评估下背部（竖脊肌）、小腿（腓肠肌）和肩部区域（三角肌）的压力疼痛阈值 (PPT)。实现多元回归模型，我们测试了假定的脆弱性因素对全身炎症期间肌肉骨骼痛觉过敏的贡献，包括促炎细胞因子的急性变化、状态焦虑和情绪，以及预先存在的焦虑和抑郁症状。内毒素应用导致血浆细胞因子、状态焦虑和消极情绪显着增加，并显着降低所有肌肉群的 PPT。回归模型显示，更高的 HADS 焦虑评分预测了更大的竖脊肌 PPT 变化。较高的 TNF-α 浓度成为腓肠肌 PPT 变化的预测因子，更明显的 TNF-α 增加和更高的 HADS 焦虑是三角肌 PPT 的预测因子。HADS 分数作为平均 PPT 分数（跨所有身体部位计算）的预测指标出现。一起，我们的结果表明，全身炎症期间的肌肉骨骼痛觉过敏与促炎细胞因子有关，特别是 TNF-α。重要的是，亚临床焦虑症状（即使在这群健康志愿者中处于低水平和正常范围内）可能会导致炎症引起的痛觉过敏，使个体更容易受到全身炎症的不利影响。