Abstract
The voltage-gated sodium channel NAV1.8 is expressed in primary nociceptive neurons and is involved in pain transmission. Mutations in the SCN10A gene (encoding NAV1.8 channel) have been identified in patients with idiopathic painful small fiber neuropathy (SFN) including the SCN10AG1662S gain-of-function mutation. However, the role of this mutation in pain sensation remains unknown. We have generated the first mouse model for the G1662S mutation by using homologous recombination in embryonic stem cells. The corresponding Scn10aG1663S mouse line has been analyzed for Scn10a expression, intraepidermal nerve fiber density (IENFD), and nociception using behavioral tests for thermal and mechanical sensitivity. The Scn10aG1663S mutants had a similar Scn10a expression level in dorsal root ganglia (DRG) to their wild-type littermates and showed normal IENFD in hindpaw skin. Mutant mice were more sensitive to touch than wild types in the von Frey test. In addition, sexual dimorphism was observed for several pain tests, pointing to the relevance of performing the phenotypical assessment in both sexes. Female homozygous mutants tended to be more sensitive to cooling stimuli in the acetone test. For heat sensitivity, male homozygous mutants showed shorter latencies to radiant heat in the Hargreaves test while homozygous females had longer latencies in the tail flick test. In addition, mutant males displayed a shorter reaction latency on the 54°C hot plate. Collectively, Scn10aG1663S mutant mice show a moderate but consistent increased sensitivity in behavioral tests of nociception. This altered nociception found in Scn10aG1663S mice demonstrates that the corresponding G1662 mutation of SCN10A found in SFN patients with pain contributes to their pain symptoms.
Highlights
Neuropathic pain “arises as a direct consequence of a lesion or diseases affecting the somatosensory system” as defined by IASP (Treede et al, 2008; Woolf, 2010; Brouwer et al, 2015)
Both transcripts were expressed in the dorsal root ganglia (DRG) of wt or G1663S/G1663S mutant mice respectively and in both sexes, indicating that the mutation did not alter the Scn10a expression
Our results collectively indicate that the Scn10aG1663S mutant mice have an enhanced pain sensitivity toward mechanical, heat, and cold stimuli in some behavioral tests, which correlate with the pain symptoms of the small fiber neuropathy (SFN) patients carrying the same mutation
Summary
Neuropathic pain “arises as a direct consequence of a lesion or diseases affecting the somatosensory system” as defined by IASP (Treede et al, 2008; Woolf, 2010; Brouwer et al, 2015). It affects 7% of the general population and 40% of patients with neurological diseases (Bouhassira, 2019). Tissue damage or injury can lead to changes in expression of sodium channel subunits in the sensory neurons, leading to an imbalance between excitatory and inhibitory signaling These modifications will affect pain thresholds and activity resulting in hyper- or hyposensitivity to pain (Nassar et al, 2005; Colloca et al, 2017)
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