Visceral and somatic pain modalities reveal NaV 1.7-independent visceral nociceptive pathways.
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Voltage-gated sodium channel NaV 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 NaV 1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV 1.7 knockout mouse (NaV 1.7(Nav1.8) ) and selective small-molecule NaV 1.7 antagonist PF-5198007. NaV 1.7(Nav1.8) mice showed normal nociceptive behaviours 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 NaV 1.7(Nav1.8) and littermate controls. Loss, or blockade, of NaV 1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV 1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV 1.7 mRNA transcripts in nearly all retrogradely-labelled colonic neurons suggesting redundancy in function. By contrast, using comparative somatic behavioral models we identify that genetic deletion of NaV 1.7 (in NaV 1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV 1.7 antagonist PF-5198007. Our data demonstrates that NaV 1.7 (in NaV 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 advocates that pharmacological block of NaV 1.7 alone in the viscera may be insufficient in targeting chronic visceral pain. This article is protected by copyright. All rights reserved.
AuthorsHockley, JRF; González-Cano, R; McMurray, S; Tejada-Giraldez, MA; McGuire, C; Torres, A; Wilbrey, AL; Cibert-Goton, V; Nieto, FR; Pitcher, T; Knowles, CH; Baeyens, JM; Wood, JN; Winchester, WJ; Bulmer, DC; Cendán, CM; McMurray, G
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