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The Journal of Neuroscience, January 4, 2006, 26(1):246-255; doi:10.1523/JNEUROSCI.3858-05.2006
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Cellular/Molecular
Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-
Xiaochun Jin and
Robert W. Gereau, IV
Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110
Tumor necrosis factor- (TNF) is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain conditions. TNF can have long-lasting effects by regulating the expression of a variety of inflammatory mediators, including other cytokines and TNF itself. However, the speed with which TNF induces tactile and thermal hypersensitivity suggests that transcriptional regulation cannot fully account for its sensitizing effects, and some recent findings suggest that TNF may act directly on primary afferent neurons to induce pain hypersensitivity. In the present study, we show that peripheral administration of TNF induces thermal hypersensitivity in wild-type mice but not in transient receptor potential vanilloid receptor TRPV1–/– mice. In contrast, TNF produced equivalent mechanical hypersensitivity in TRPV1–/– mice and wild-type littermates, suggesting a role for TRPV1 in TNF-induced thermal, but not mechanical, hypersensitivity. Because tetrodotoxin (TTX)-resistant Na+ channels are a critical site of modulation underlying mechanical hypersensitivity in inflammatory and neuropathic pain conditions, we tested the effects of TNF on these channels in isolated mouse dorsal root ganglion (DRG) neurons. We report that acute application of TNF rapidly enhances TTX-resistant Na+ currents in isolated DRG neurons. This potentiation of TTX-resistant currents by TNF is dramatically reduced in DRG neurons from TNF receptor 1 (TNFR1) knock-out mice and is blocked by the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]. Mechanical hypersensitivity induced by peripherally applied TNF is also significantly reduced by SB202190. These results suggest that TNF may induce acute peripheral mechanical sensitization by acting directly on TNFR1 in primary afferent neurons, resulting in p38-dependent modulation of TTX-resistant Na+ channels.
Key words: pain; MAPK; TNF; nociceptor; DRG; Nav1.8; phosphorylation; sensitization
Received Sep 12, 2005;
revised November 4, 2005;
accepted November 8, 2005.
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