Two independent mouse lines carrying the Nav1.7-I228M gain-of-function variant display DRG neuron hyperexcitability but a minimal pain phenotype

Small-fiber neuropathy (SFN), characterized by distal unmyelinated/thinly-myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Nav1.7 that produce DRG neuron hyperexcitability are present in 5-10% of patients with idiopathic painful SFN. We created two independent knock-in mouse-lines carrying the Nav1.7-I228M gain-of-function variant, found in idiopathic SFN. Whole-cell patch-clamp and multi-electrode-array recordings show that Nav1.7-I228M knock-in DRG neurons are hyperexcitable compared to wild-type littermate-control neurons, but in spite of this, Nav1.7-I228M mice do not display mechanical or thermal-hyperalgesia or intraepidermal nerve-fiber loss in vivo. Therefore, while these two Nav1.7-I228M knock-in mouse lines recapitulate the DRG neuron hyperexcitability associated with gain-of function mutations in Nav1.7, they do not recapitulate the pain or neuropathy phenotypes seen in patients. We suggest that the relationship between hyper-excitability in sensory neurons and the pain experienced by these patients may be more complex than previously appreciated and highlights the challenges in modelling channelopathy pain disorders in mice.