Pain is a widespread motivation for seeking healthcare and stands as a substantial global public health concern. Despite comprehensive investigations into the mechanisms of pain sensitization induced by inflammation, efficacious treatments options remain scarce Neutrophil extracellular traps (NETs) have been associated with the progression and tissue damage of diverse inflammatory diseases. This study aims to explore the impact of NETs on the progression of inflammatory pain and explore potential therapeutic approaches. Initially, we observed neutrophil infiltration and the formation of NETs in the left hind paw of mice with inflammatory pain induced by complete Freund's adjuvant (CFA). Furthermore, we employed the peptidyl arginine deiminase 4 (PAD4) inhibitor Cl-amidine (diluted at 50 mg/kg in saline, administered via tail vein injection once daily for three days) to impede NETs formation and administered DNase1 (diluted at 10 mg/kg in saline, once daily for three days) to break down NETs. We investigated the pathological importance of peripheral NETs formation in inflammatory pain and its influence on the activation of spinal dorsal horn microglia. The findings indicate that neutrophils infiltrating locally generate NETs, leading to an increased release of inflammatory mediators that worsen peripheral inflammatory reactions. Consequently, this results in the transmission of more harmful peripheral stimuli to the spinal cord, triggering microglial activation and NF-κB phosphorylation, thereby escalating neuroinflammation and fostering pain sensitization. Suppression of peripheral NETs can mitigate peripheral inflammation in mice with inflammatory pain, reverse mechanical and thermal hypersensitivity by suppressing microglial activation in the spinal cord, ultimately diminishing inflammatory pain. In conclusion, these discoveries propose that obstructing or intervening with NETs introduces a novel therapeutic avenue for addressing inflammatory pain.

中文翻译：

---

中性粒细胞胞外陷阱作为治疗炎性疼痛的独特靶点

疼痛是寻求医疗保健的普遍动机，也是全球重大的公共卫生问题。尽管对炎症引起的疼痛敏化机制进行了全面的研究，但有效的治疗选择仍然很少。中性粒细胞胞外陷阱（NET）与多种炎症性疾病的进展和组织损伤有关。本研究旨在探讨 NET 对炎性疼痛进展的影响并探索潜在的治疗方法。最初，我们在完全弗氏佐剂（CFA）诱导的炎症性疼痛小鼠的左后爪中观察到中性粒细胞浸润和 NET 的形成。此外，我们使用肽基精氨酸脱亚胺酶 4 (PAD4) 抑制剂 Cl-脒（在盐水中稀释为 50 mg/kg，通过尾静脉注射给药，每天一次，持续三天）来阻止 NET 形成，并施用 DNase1（稀释为 10 mg/kg）。千克盐水中，每天一次，持续三天）以分解 NET。我们研究了外周 NET 形成在炎性疼痛中的病理重要性及其对脊髓背角小胶质细胞活化的影响。研究结果表明，局部浸润的中性粒细胞会产生 NET，导致炎症介质释放增加，从而加剧外周炎症反应。因此，这会导致更多有害的外周刺激传递到脊髓，触发小胶质细胞激活和 NF-κB 磷酸化，从而加剧神经炎症并促进疼痛敏化。抑制外周 NET 可以减轻炎症性疼痛小鼠的外周炎症，通过抑制脊髓中的小胶质细胞激活来逆转机械和热过敏，最终减轻炎症性疼痛。总之，这些发现表明，阻碍或干预 NET 为解决炎症性疼痛提供了一种新的治疗途径。