Dissecting the role of sodium currents in visceral sensory neurons in a model of chronic hyperexcitability using Nav1.8 and Nav1.9 null mice

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Abstract
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 Nav1.8 and Nav1.9 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 Nav1.9 and Nav1.8 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 Nav1.9 and Nav1.8 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 Nav1.9−/− mice, but hyperexcitability was absent and APs were blunted in Nav1.8−/− mice. This study identifies a critical role for Nav1.8 in chronic post‐infectious visceral hyperexcitability, with no contribution from Nav1.9. Nb infection‐induced hyperexcitability is not observed in Nav1.8−/− mice, but is still present in Nav1.9−/− mice. It is not clear whether hyperexcitability is due to a change in the function of Nav1.8 channels or a change in the number of Nav1.8 channels.