期刊
PAIN
卷 152, 期 12, 页码 2881-2891出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.pain.2011.09.020
关键词
Allodynia; Arthritis; Astrocytes; Inflammation; Microglia; Toll-like receptor 4 (TLR4)
资金
- National Institutes of Health [NS16541, DA02110, GM064611, GM069338, 2T32GM007752-31]
- Arthritis Foundation
- Swedish Research Council
- Swedish Foundation for Strategic Research
- ScanDesign International Association for Studies of Pain
- Marie Curie International Reintegration grant
- Olle Engkvist Byggmastares Foundation
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 mu g), 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-Delta(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 mu g) 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. (C) 2011 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据