Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis

• Published in: Pain (Amsterdam) Vol. 152; no. 12; pp. 2881 - 2891
• Main Authors: Christianson, Christina A., Dumlao, Darren S., Stokes, Jennifer A., Dennis, Edward A., Svensson, Camilla I., Corr, Maripat, Yaksh, Tony L.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier B.V 01.12.2011; Elsevier
• Subjects: Allodynia; Animals; Arthritis; Arthritis, Experimental - blood; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Astrocytes; Biological and medical sciences; Chronic Pain - blood; Chronic Pain - immunology; Chronic Pain - pathology; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Hyperalgesia - blood; Hyperalgesia - immunology; Hyperalgesia - pathology; Illness and personality; Illness, stress and coping; Inflammation; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - blood; Inflammation Mediators - physiology; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Psychology and medicine; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Signal Transduction - immunology; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Spinal Cord - immunology; Spinal Cord - metabolism; Spinal Cord - pathology; Toll-like receptor 4 (TLR4); Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - deficiency; Toll-Like Receptor 4 - physiology; Vertebrates: nervous system and sense organs; Allodynia; Toll-like receptor 4 (TLR4); Arthritis; Inflammation; Astrocytes; Microglia; Spinal cord; Methodology; Neuroglia; Diseases of the osteoarticular system; Central nervous system; Lipids; Rhodospirillaceae; Osteoarticular system; Rhodospirillales; Pain; Rhodobacter sphaeroides; Eicosanoid; Lipopolysaccharide; Bacteria; Rhodospirillineae; Biological receptor; Arachidonic acid derivatives; Hypersensitivity; Rodentia; Joint; Vertebrata; Mammalia; Mouse; Models; Sign
• ISSN: 0304-3959; 1872-6623; 1872-6623
• DOI: 10.1016/j.pain.2011.09.020

Neither Tlr4 −/− K/BxN serum transfer arthritic mice nor those administered spinal TLR4 pharmacological blockade display persistent mechanical hypersensitivity, in contrast to WT mice. 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.