| First Author | Christianson CA | Year | 2011 |
| Journal | Pain | Volume | 152 |
| Issue | 12 | Pages | 2881-2891 |
| PubMed ID | 22019135 | Mgi Jnum | J:315226 |
| Mgi Id | MGI:6829834 | Doi | 10.1016/j.pain.2011.09.020 |
| Citation | Christianson CA, et al. (2011) Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain 152(12):2881-2891 |
| abstractText | 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 mug), 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 mug) 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. |
