Two independent mouse lines carrying the Na_v1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype

Abstract

Small-fiber neuropathy (SFN), characterized by distal unmyelinated or thinly myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Na_v1.7 that produce dorsal root ganglion (DRG) neuron hyperexcitability are present in 5% to 10% of patients with idiopathic painful SFN. We created 2 independent knock-in mouse lines carrying the Na_v1.7 I228M gain-of-function variant, found in idiopathic SFN. Whole-cell patch-clamp and multielectrode array recordings show that Na_v1.7 I228M knock-in DRG neurons are hyperexcitable compared with wild-type littermate-control neurons, but despite this, Na_v1.7 I228M mice do not display mechanical or thermal hyperalgesia or intraepidermal nerve fiber loss in vivo. Therefore, although these 2 Na_v1.7 I228M knock-in mouse lines recapitulate the DRG neuron hyperexcitability associated with gain-of-function mutations in Na_v1.7, they do not recapitulate the pain or neuropathy phenotypes seen in patients. We suggest that the relationship between hyperexcitability 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.

In Brief

Two independent Na_v1.7 I228M knock-in mouse lines suggest a complicated relationship between dorsal root ganglion neuron hyperexcitability and painful neuropathy, highlighting challenges in modelling channelopathic pain disorders in mice.