AUTHOR=Xue Yaping , Kremer Mélanie , Muniz Moreno Maria del Mar , Chidiac Celeste , Lorentz Romain , Birling Marie-Christine , Barrot Michel , Herault Yann , Gaveriaux-Ruff Claire 

TITLE=The Human SCN9AR185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 15 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.913990

DOI=10.3389/fnmol.2022.913990

ISSN=1662-5099

ABSTRACT=The voltage-gated sodium channel Nav1.7 is encoded by SCN9A gene and plays a critical role in pain sensitivity. Several SCN9A gain-of-function (GOF) mutations have been found in small fiber neuropathy (SFN) patients with chronic pain, including the R185H mutation. However, for most of these variants, their involvement in pain phenotype still needs to be experimentally elucidated. In order to delineate the impact of R185H mutation on pain sensitivity, we have established the Scn9aR185H mutant mouse model using the CRISPR/Cas9 technology. The Scn9aR185H mutant mice show no cellular alteration in the dorsal root ganglia containing cell bodies of sensory neurons and no alteration of growth or global health state. Heterozygous and homozygous animals of both sexes were investigated for pain sensitivity. The mutant mice were more sensitive than wild-type mice in the tail flick and hot plate tests, acetone as well as von Frey tests for sensitivity to heat, cold and touch, respectively, although with sexual dimorphic effects. The newly developed bioinformatic pipeline Gdaphen is based on general linear model and random forest classifiers as well as multifactor analysis of mixed data, and shows the qualitative and quantitative variables contributing the most to the pain phenotype. Using Gdaphen, tail flick, Hargreaves, hot plate, acetone, cold plate and von Frey tests as well as sex and genotype were found to contribute most to the pain phenotype. Importantly, the mutant animals displayed spontaneous pain as assessed in the Conditioned Place Preference assay. Altogether, our results indicate that Scn9aR185H mice show a pain phenotype, suggesting that the SCN9A R185H mutation identified in SFN patients with chronic pain contributes to their symptoms. Therefore, we provide genetic evidence that this mutation in Nav1.7 channel plays an important role in nociception and in the pain experienced by SFN patients with this mutation. These findings should aid exploring further pain treatments based on the Nav1.7 channel.