Itch and insensitivity to pain in an Nav1.7 mutant mouse model

Abstract

Gain-of-function mutations in Nav1.7, a peripheral neuron-specific voltage-gated sodium channel encoded by the gene Scn9a, have been implicated in several genetic pain conditions in humans. These include inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN). Conversely, loss-of-function mutations in the channel have been linked to congenital insensitivity to pain (CIP). Therefore, these mutations are seen as evidence for a link between increased sodium conductance, dorsal root ganglion (DRG) neuron hyperexcitability, and pain. We used CRISPR/Cas9 to engineer an Nav1.7 gain-of-function mutation, I228M, in mice. While we observed the expected hyperexcitability in DRG neurons from these mice, these mice unexpectedly exhibited normal mechanical and thermal sensitivity in young adulthood. However, over time they developed a profound insensitivity to noxious heat, as well as a severe scratching phenotype, leading to lesions of the skin. We explored, through RNA sequencing, which sensory neurons are responsible for these phenotypic changes and found a decrease in the expression of Scn9a, as well as a striking decrease in C-low threshold mechanoreceptor- (cLTMR) associated gene expression, potentially suggesting a new role for this DRG neuron subtype in the context of Nav1.7 dysfunction. Additionally, we utilized these mice as a model to probe, at high spatial and temporal resolution, the dynamics of scratching itself. We aimed to expand beyond standard measures of scratching bouts and identify a metric that correlates with and explains the degree of damage to the skin. Using these approaches, here we investigated the relationship between aberrant Nav1.7 activity, itch, and pain.