More than a quarter of veterans of the 1990-1991 Persian Gulf War suffer from Gulf War Illness (GWI), a chronic, multi-symptom illness that commonly includes musculoskeletal pain. Exposure to a range of toxic chemicals, including sarin nerve agent, are a suspected root cause of GWI. Moreover, such chemical exposures induce a neuroinflammatory response in rodents, which has been linked to several GWI symptoms in rodents and veterans with GWI. To date, a neuroinflammatory basis for pain associated with GWI has not been investigated. Here, we evaluated development of nociceptive hypersensitivity in a model of GWI. Male Sprague Dawley rats were treated with corticosterone in the drinking water for 7 days, to mimic high physiological stress, followed by a single injection of the sarin nerve agent surrogate, diisopropyl fluorophosphate. These exposures alone were insufficient to induce allodynia. However, an additional sub-threshold challenge (a single intramuscular injection of pH 4 saline) induced long-lasting, bilateral allodynia. Such allodynia was associated with elevation of markers for activated microglia/macrophages (CD11b) and astrocytes/satellite glia (GFAP) in the lumbar dorsal spinal cord and dorsal root ganglia (DRG). Additionally, Toll-like receptor 4 (TLR4) mRNA was elevated in the lumbar dorsal spinal cord, while IL-1β and IL-6 were elevated in the lumbar dorsal spinal cord, DRG, and gastrocnemius muscle. Demonstrating a casual role for such neuroinflammatory signaling, allodynia was reversed by treatment with either minocycline, the TLR4 inhibitor (+)-naltrexone, or IL-10 plasmid DNA. Together, these results point to a role for neuroinflammation in male rats in the model of musculoskeletal pain related to GWI. Therapies that alleviate persistent immune dysregulation may be a strategy to treat pain and other symptoms of GWI.

中文翻译：

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神经免疫信号在海湾战争疾病相关疼痛大鼠模型中的作用


超过四分之一的 1990-1991 波斯湾战争退伍军人患有海湾战争病 (GWI)，这是一种慢性、多症状疾病，通常包括肌肉骨骼疼痛。接触一系列有毒化学物质，包括沙林神经毒剂，可能是 GWI 的根本原因。此外，此类化学物质暴露会引起啮齿类动物的神经炎症反应，这与啮齿类动物和患有 GWI 的退伍军人的几种 GWI 症状有关。迄今为止，尚未研究与 GWI 相关的疼痛的神经炎症基础。在这里，我们评估了 GWI 模型中伤害性超敏反应的发展。雄性 Sprague Dawley 大鼠在饮用水中接受皮质酮治疗 7 天，以模拟高生理应激，然后单次注射沙林神经毒剂替代物二异丙基氟磷酸盐。仅这些暴露不足以诱发异常性疼痛。然而，额外的亚阈值挑战（单次肌内注射 pH 4 盐水）会引起持久的双侧异常性疼痛。这种异常性疼痛与腰背脊髓和背根神经节（DRG）中活化的小胶质细胞/巨噬细胞（CD11b）和星形胶质细胞/卫星胶质细胞（GFAP）标记物的升高有关。此外，腰背脊髓中 Toll 样受体 4 (TLR4) mRNA 升高，而腰背脊髓、背根神经节和腓肠肌中 IL-1β 和 IL-6 升高。异常性疼痛通过米诺环素、TLR4 抑制剂 (+)-纳曲酮或 IL-10 质粒 DNA 治疗逆转，这表明这种神经炎症信号传导具有偶然作用。总之，这些结果表明了雄性大鼠神经炎症在与 GWI 相关的肌肉骨骼疼痛模型中的作用。 缓解持续性免疫失调的疗法可能是治疗 GWI 疼痛和其他症状的策略。