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The Journal of Neuroscience, December 13, 2006, 26(50):12852-12860; doi:10.1523/JNEUROSCI.4015-06.2006
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Cellular/Molecular
The Voltage-Gated Sodium Channel Nav1.9 Is an Effector of Peripheral Inflammatory Pain Hypersensitivity
Fumimasa Amaya,1 Haibin Wang,1 Michael Costigan,1 Andrew J. Allchorne,1 Jon P. Hatcher,2 Julie Egerton,2 Tania Stean,2 Valerie Morisset,2 David Grose,3 Martin J. Gunthorpe,2 Iain P. Chessell,2 Simon Tate,3 Paula J. Green,2 andClifford J. Woolf1 1Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, 2Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, CM19 5AW, United Kingdom, and 3Discovery Research, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, United Kingdom
Correspondence should be addressed to Clifford J Woolf, Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129. Email: cwoolf{at}partners.org
We used a mouse with deletion of exons 4, 5, and 6 of the SCN11A (sodium channel, voltage-gated, type XI,
) gene that encodes the voltage-gated sodium channel Nav1.9 to assess its contribution to pain. Nav1.9 is present in nociceptor sensory neurons that express TRPV1, bradykinin B2, and purinergic P2X3 receptors. In Nav1.9–/– mice, the non-inactivating persistent tetrodotoxin-resistant sodium TTXr-Per current is absent, whereas TTXr-Slow is unchanged. TTXs currents are unaffected by the mutation of Nav1.9. Pain hypersensitivity elicited by intraplantar administration of prostaglandin E2, bradykinin, interleukin-1ß, capsaicin, and P2X3 and P2Y receptor agonists, but not NGF, is either reduced or absent in Nav1.9–/– mice, whereas basal thermal and mechanical pain sensitivity is unchanged. Thermal, but not mechanical, hypersensitivity produced by peripheral inflammation (intraplanatar complete Freund's adjuvant) is substantially diminished in the null allele mutant mice, whereas hypersensitivity in two neuropathic pain models is unchanged in the Nav1.9–/– mice. Nav1.9 is, we conclude, an effector of the hypersensitivity produced by multiple inflammatory mediators on nociceptor peripheral terminals and therefore plays a key role in mediating peripheral sensitization.
Key words: sensory neuron; peripheral sensitization; inflammation; nociceptor; pain; sodium channel
Received Sept. 14, 2006; revised Oct. 19, 2006; accepted Oct. 20, 2006.
Correspondence should be addressed to Clifford J Woolf, Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129. Email: cwoolf{at}partners.org
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