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Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system

Shields, Shannon D.a; Ahn, Hye-Sooka; Yang, Yanga; Han, Chongyanga; Seal, Rebecca P.b; Wood, John N.c; Waxman, Stephen G.a; Dib-Hajj, Sulayman D.a,*

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doi: 10.1016/j.pain.2012.04.022
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Summary Nav1.8 is expressed in 75% of all primary somatosensory afferents, including not only nociceptors but also C-and A-fiber low-threshold mechanoreceptors.

ABSTRACT A vast diversity of salient cues is sensed by numerous classes of primary sensory neurons, defined by specific neuropeptides, ion channels, or cytoskeletal proteins. Recent evidence has demonstrated a correlation between the expression of some of these molecular markers and transmission of signals related to distinct sensory modalities (eg, heat, cold, pressure). Voltage-gated sodium channel Nav1.8 has been reported to be preferentially expressed in small-diameter unmyelinated sensory afferents specialized for the detection of noxious stimuli (nociceptors), and Nav1.8-Cre mice have been widely used to investigate gene function in nociceptors. However, the identity of neurons in which Cre-mediated recombination occurs in these animals has not been resolved, and whether expression of Nav1.8 in these neurons is dynamic during development is not known, rendering interpretation of conditional knockout mouse phenotypes problematic. Here, we used genetics, immunohistochemistry, electrophysiology, and calcium imaging to precisely characterize the expression of Nav1.8 in the peripheral nervous system. We demonstrate that 75% of dorsal root ganglion (DRG) neurons express Nav1.8-Cre, including >90% of neurons expressing markers of nociceptors and, unexpectedly, a large population (∼40%) of neurons with myelinated A fibers. Furthermore, analysis of DRG neurons’ central and peripheral projections revealed that Nav1.8-Cre is not restricted to nociceptors but is also expressed by at least 2 types of low-threshold mechanoreceptors essential for touch sensation, including those with C and Aβ fibers. Our results indicate that Nav1.8 underlies electrical activity of sensory neurons subserving multiple functional modalities, and call for cautious interpretation of the phenotypes of Nav1.8-Cre-driven conditional knockout mice.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

aDepartment of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA

bDepartment of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA

cMolecular Nociception Group, University College London, London, UK

*Corresponding author. Address: Center for Neuroscience and Regeneration Research, Veterans’ Affairs Connecticut Healthcare System, 950 Campbell Ave., Bldg 34, West Haven, CT 06516, USA. Tel.: +1 203 937 3802; fax: +1 203 937 3801.

E-mail address:Sulayman.Dib-Hajj@Yale.edu

© 2012 Lippincott Williams & Wilkins, Inc.
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