Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system.
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 Na(v)1.8 has been reported to be preferentially expressed in small-diameter unmyelinated sensory afferents specialized for the detection of noxious stimuli (nociceptors), and Na(v)1.8-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 Na(v)1.8 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 Na(v)1.8 in the peripheral nervous system. We demonstrate that 75% of dorsal root ganglion (DRG) neurons express Na(v)1.8-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 Na(v)1.8-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 Na(v)1.8 underlies electrical activity of sensory neurons subserving multiple functional modalities, and call for cautious interpretation of the phenotypes of Na(v)1.8-Cre-driven conditional knockout mice.
Department 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 Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA Molecular Nociception Group, University College London, London, UK.
Shannon D
SD
Shields
Hye-Sook
HS
Ahn
Yang
Y
Yang
Chongyang
C
Han
Rebecca P
RP
Seal
John N
JN
Wood
Stephen G
SG
Waxman
Sulayman D
SD
Dib-Hajj
D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000378:metabolism*; D014018:Tissue Distribution
D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse