Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, La Jolla, CA, USA.
Pain. 2011 Dec;152(12):2881-2891. doi: 10.1016/j.pain.2011.09.020. Epub 2011 Oct 21.
Persistent pain after resolution of clinically appreciable signs of arthritis poses a therapeutic challenge, and immunosuppressive therapies do not meet this medical need. To investigate this conversion to persistent pain, we utilized the K/BxN serum transfer arthritis model, which has persistent mechanical hypersensitivity despite the resolution of visible inflammation. Toll-like receptor (TLR) 4 has been implicated as a potential therapeutic target in neuropathic and other pain models. We compared the relative courses of serum transfer arthritis and mechanical hypersensitivity in wild type (WT) and Tlr4(-/-) mice. K/BxN serum transfer induced similar joint swelling and inflammation from days 4-22 in WT and Tlr4(-/-) mice. Unlike WT mice, Tlr4(-/-) mice displayed a significant reversal in mechanical hypersensitivity and diminished appearance of glial activation markers after resolution of peripheral inflammation. Intrathecal (IT) delivery of a TLR4 antagonist, lipopolysaccharide Rhodobacter sphaeroides (LPS-RS; 10 μg), on days 6, 9, and 12 abrogated the transition to persistent mechanical hypersensitivity in WT arthritic mice, while later administration had no impact. We utilized a lipidomics liquid chromatography tandem mass spectrometry methodology to determine spinal cord profiles of bioactive lipid species after early LPS-RS treatment compared to vehicle-treated control animals. WT arthritic mice had reduced spinal levels of the anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) on day 6, compared to IT LPS-RS-treated mice. Direct IT application of 15d-PGJ(2) (0.5 μg) on day 6 improved mechanical hypersensitivity in arthritic mice within 15 min. Hence, TLR4 signaling altered spinal bioactive lipid profiles in the serum transfer model and played a critical role in the transition from acute to chronic postinflammatory mechanical hypersensitivity.
关节炎临床明显体征消退后持续性疼痛带来了治疗挑战，而免疫抑制疗法无法满足这一医疗需求。为了研究这种向持续性疼痛的转变，我们利用 K/BxN 血清转移关节炎模型，该模型尽管存在可见炎症消退，但仍存在持续性机械性超敏反应。Toll 样受体 (TLR)4 已被认为是神经病理性和其他疼痛模型中的一个潜在治疗靶点。我们比较了野生型 (WT) 和 Tlr4(-/-) 小鼠的血清转移关节炎和机械性超敏反应的相对过程。K/BxN 血清转移在 WT 和 Tlr4(-/-) 小鼠中诱导了相似的关节肿胀和炎症，从第 4 天到第 22 天。与 WT 小鼠不同的是，Tlr4(-/-) 小鼠在周围炎症消退后，机械性超敏反应出现显著逆转，神经胶质激活标志物的出现也减少。在第 6、9 和 12 天鞘内 (IT) 给予 TLR4 拮抗剂脂多糖 Rhodobacter sphaeroides(LPS-RS;10 μg)可阻断 WT 关节炎小鼠向持续性机械性超敏反应的转变，而后期给药则无影响。我们利用脂质组学液相色谱串联质谱方法，与载体处理的对照动物相比，确定早期 LPS-RS 处理后脊髓生物活性脂质种类的图谱。与 IT LPS-RS 处理的小鼠相比，WT 关节炎小鼠在第 6 天脊髓中抗炎性前列腺素 15-脱氧-Δ(12,14)-PGJ(2)(15d-PGJ(2))水平降低。在第 6 天直接 IT 给予 15d-PGJ(2)(0.5 μg)可在 15 分钟内改善关节炎小鼠的机械性超敏反应。因此，TLR4 信号改变了血清转移模型中的脊髓生物活性脂质图谱，并在急性向慢性炎症后机械性超敏反应的转变中发挥了关键作用。
