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Tetrodotoxin-resistant (TTX-R) sodium currents have been proposed to underlie sensory neuronal hyperexcitability in acute inflammatory models, but their role in chronic models is unknown. Since no pharmacological tools to separate TTX-R currents are available, this study employs Na v 1.8 and Na v 1.9 null mice to evaluate these currents roles in a chronic hyperexcitability model after the resolution of an inflammatory insult. Transient jejunitis was induced by infection with Nippostrongylus brasiliensis (Nb) in Na v 1.9 and Na v 1.8 null, wild-type and naïve mice. Retrogradely labelled dorsal root ganglia (DRG) neurons were harvested on day 20-24 post-infection for patch clamp recording. Rheobase and action potential (AP) parameters were recorded as measures of excitability, and Na v 1.9 and Na v 1.8 currents were recorded. DRG neuronal excitability was significantly increased in post-infected mice compared to sham animals, despite the absence of ongoing inflammation (sham = 1.9 ± 0.3, infected = 3.6 ± 0.7 APs at 2× rheobase, P = 0.02). Hyperexcitability was associated with a significantly increased amplitude of TTX-R currents. Hyperexcitability was maintained in Na v 1.9 -/-mice, but hyperexcitability was absent and APs were blunted in Na v 1.8 -/-mice. This study identifies a critical role for Na v 1.8 in chronic post-infectious visceral hyperexcitability, with no contribution from Na v 1.9. Nb infection-induced hyperexcitability is not observed in Na v 1.8 -/-mice, but is still present in Na v 1.9 -/-mice. It is not clear whether hyperexcitability is due to a change in the function of Na v 1.8 channels or a change in the number of Na v 1.8 channels.

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