ABSTRACT:Rheumatoid arthritis-associated pain is poorly managed, often persisting when joint inflammation is pharmacologically controlled. Comparably, in the mouse K/BxN serum-transfer model of inflammatory arthritis, hind paw nociceptive hypersensitivity occurs with ankle joint swelling (5 days after immunisation) persisting after swelling has resolved (25 days after immunisation). In this study, lipid mediator (LM) profiling of lumbar dorsal root ganglia (DRG), the site of sensory neuron cell bodies innervating the ankle joints, 5 days and 25 days after serum transfer demonstrated a shift in specialised proresolving LM profiles. Persistent nociception without joint swelling was associated with low concentrations of the specialised proresolving LM Maresin 1 (MaR1) and high macrophage numbers in DRG. MaR1 application to cultured DRG neurons inhibited both capsaicin-induced increase of intracellular calcium ions and release of calcitonin gene-related peptide in a dose-dependent manner. Furthermore, in peritoneal macrophages challenged with lipopolysaccharide, MaR1 reduced proinflammatory cytokine expression. Systemic MaR1 administration caused sustained reversal of nociceptive hypersensitivity and reduced inflammatory macrophage numbers in DRG. Unlike gabapentin, which was used as positive control, systemic MaR1 did not display acute antihyperalgesic action. Therefore, these data suggest that MaR1 effects observed after K/BxN serum transfer relate to modulation of macrophage recruitment, more likely than to direct actions on sensory neurons. Our study highlights that, in DRG, aberrant proresolution mechanisms play a key role in arthritis joint pain dissociated from joint swelling, opening novel approaches for rheumatoid arthritis pain treatment.

译文

摘要: 类风湿性关节炎相关疼痛管理不善,当关节炎症得到药理学控制时,通常会持续。相比之下,在炎症性关节炎的小鼠K/BxN血清转移模型中,后爪伤害性超敏反应发生,踝关节肿胀 (免疫后5天) 在肿胀消退后 (免疫后25天) 持续存在。在这项研究中,血清转移后5天和25天,腰背根神经节 (DRG) 的脂质介体 (LM) 分析显示,感觉神经元细胞体支配踝关节的部位在专门的前移LM谱中发生了变化。持续的无关节肿胀的伤害感受与低浓度的特殊预溶解的LM marresin 1 (MaR1) 和DRG中的高巨噬细胞数量有关。将MaR1应用于培养的DRG神经元以剂量依赖性方式抑制辣椒素诱导的细胞内钙离子增加和降钙素基因相关肽的释放。此外,在受到脂多糖攻击的腹膜巨噬细胞中,MaR1降低了促炎细胞因子的表达。系统性MaR1给药可导致伤害性超敏反应的持续逆转,并减少DRG中的炎性巨噬细胞数量。与用作阳性对照的加巴喷丁不同,系统性MaR1不显示急性抗痛觉过敏作用。因此,这些数据表明,K/BxN血清转移后观察到的MaR1效应与巨噬细胞募集的调节有关,比直接对感觉神经元的作用更可能。我们的研究强调,在DRG中,异常的溶解机制在关节炎关节痛与关节肿胀分离中起着关键作用,为类风湿性关节炎疼痛的治疗开辟了新的途径。

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