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 α 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 Na_V 1.7 (in Na_V 1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective Na_V 1.7 antagonist PF-5198007. Our data demonstrate that Na_V 1.7 (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.

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