Joint pain is a distressing symptom of arthritis, and it is frequently persistent even after treatments which reduce local inflammation. Continuous production of algogenic factors activate/sensitize nociceptors in the joint structures and contribute to persistent pain, a challenging and difficult condition to treat. TNF is a crucial cytokine for the pathogenesis of several rheumatic diseases, and its inhibition is a mainstay of treatment to control joint symptoms, including pain. Here, we sought to investigate the inflammatory changes and the role of TNF in dorsal root ganglia (DRG) during persistent hypernociception after the resolution of acute joint inflammation. Using a model of antigen-induced arthritis, the peak of joint inflammation occurred 12-24 h after local antigen injection and was characterized by an intense influx of neutrophils, pro-inflammatory cytokine production, and joint damage. We found that inflammatory parameters in the joint returned to basal levels between 6 and 8 days after antigen-challenge, characterizing the resolving phase of joint inflammation. Mechanical hyperalgesia was persistent up to 14 days after joint insult. The persistent nociception was associated with the inflammatory status of DRG after cessation of acute joint inflammation. The late state of neuroinflammation in the ipsilateral side was evidenced by gene expression of TNF, TNFR2, IL-6, IL-1β, CXCL2, COX2, and iNOS in lumbar DRG (L3-L5) and leukocyte adhesion in the lumbar intumescent vessels between days 6 and 8. Moreover, there were signs of resident macrophage activation in DRG, as evidenced by an increase in Iba1-positive cells. Intrathecal or systemic injection of etanercept, an agent clinically utilized for TNF neutralization, at day 7 post arthritis induction, alleviated the persistent joint hyperalgesia by specific action in DRG. Our data suggest that neuroinflammation in DRG after the resolution of acute joint inflammation drives continuous neural sensitization resulting in persistent joint nociception in a TNF-dependent mechanism.

中文翻译：

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消炎后，感觉神经节特异性TNF表达与持续伤害感受有关。

关节痛是一种令人痛苦的关节炎症状，即使在减少局部炎症的治疗后，关节痛也经常持续存在。持续产生促生性激素因子会激活/敏化关节结构中的伤害感受器，并导致持续的疼痛，这是一种具有挑战性和难于治疗的疾病。TNF是几种风湿病发病机理中至关重要的细胞因子，其抑制作用是控制关节症状（包括疼痛）的主要手段。在这里，我们寻求调查急性关节炎症消退后持续性高伤害感受期间炎症变化和TNF在背根神经节（DRG）中的作用。使用抗原诱发的关节炎模型，局部注射抗原后12-24小时出现关节发炎的高峰，其特征是嗜中性粒细胞大量涌入，促炎性细胞因子的产生，以及关节损伤。我们发现，在抗原攻击后6至8天之间，关节中的炎症参数恢复到基础水平，这是关节炎症的解决阶段的特征。机械痛觉过敏持续至关节损伤后14天。持续的伤害感受与急性关节炎症停止后DRG的炎症状态有关。腰部DRG（L3-L5）中TNF，TNFR2，IL-6，IL-1β，CXCL2，COX2和iNOS的基因表达以及腰突血管之间的白细胞粘附证明了同侧神经炎症的晚期状态第6天和第8天。此外，DRG中存在巨噬细胞活化的迹象，如Iba1阳性细胞增加所证明。鞘内或全身注射依那西普，一种在TNF诱导后第7天被临床用于TNF中和的药物，通过DRG中的特异性作用减轻了持续性关节痛觉过敏。我们的数据表明，急性关节发炎消退后，DRG中的神经发炎会导致持续的神经敏化，从而导致以TNF依赖性机制持续发生关节痛。