Visceral and somatic pain modalities reveal NaV1.7-independent visceral nociceptive pathways

Voltage-gated sodium channel Na(V)1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of Na(V)1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific Na(V)1.7 knockout mouse (Na(V)1.7(Nav1.8)) and selective small-molecule Na(V)1.7 antagonist PF-5198007. Na(V)1.7(Nav1.8) mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both Na(V)1.7(Nav1.8) and littermate controls. Loss, or blockade, of Na(V)1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of Na(V)1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel alpha subunits revealed Na(V)1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV1.7 (in Na(V)1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV1.7 antagonist PF-5198007. Our data demonstrate that NaV1.7 (in Na(V)1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of Na(V)1.7 alone in the viscera may be insufficient in targeting chronic visceral pain.