Acute P38-mediated Modulation of Tetrodotoxin-resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-alpha.
From: Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publish Date: Jan 2006
- ISSN: 1529-2401
- Volume: 26
- Issue: 1
- Pages: 246-55
- Medium: Internet
- Language: English
- Citation (JAMA): Jin Xiaochun, Gereau Robert W, et al. Acute P38-mediated Modulation of Tetrodotoxin-resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-alpha.. J. Neurosci. Jan 2006;26:246-55
Abstract
Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain conditions. TNFalpha can have long-lasting effects by regulating the expression of a variety of inflammatory mediators, including other cytokines and TNFalpha itself. However, the speed with which TNFalpha induces tactile and thermal hypersensitivity suggests that transcriptional regulation cannot fully account for its sensitizing effects, and some recent findings suggest that TNFalpha may act directly on primary afferent neurons to induce pain hypersensitivity. In the present study, we show that peripheral administration of TNFalpha induces thermal hypersensitivity in wild-type mice but not in transient receptor potential vanilloid receptor TRPV1(-/-) mice. In contrast, TNFalpha produced equivalent mechanical hypersensitivity in TRPV1(-/-) mice and wild-type littermates, suggesting a role for TRPV1 in TNFalpha-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 TNFalpha on these channels in isolated mouse dorsal root ganglion (DRG) neurons. We report that acute application of TNFalpha rapidly enhances TTX-resistant Na+ currents in isolated DRG neurons. This potentiation of TTX-resistant currents by TNFalpha 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 TNFalpha is also significantly reduced by SB202190. These results suggest that TNFalpha 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.
Mesh Headings (Keywords): Animals, Cells, Cultured, Dose-Response Relationship, Drug, Drug Resistance, Enzyme Inhibitors, Ganglia, Spinal, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Knockout, Neurons, Afferent, Sodium Channels, Tetrodotoxin, Tumor Necrosis Factor-alpha, p38 Mitogen-Activated Protein Kinases
Check for Full Text / PubMed Unique Identifier (PMID): 16399694
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