title: Visceral and somatic pain modalities reveal NaV1.7-independent visceral nociceptive pathways.
abstract: Voltage-gated sodium channels play a fundamental role in determining neuronal excitability. Specifically, voltage-gated sodium channel subtype NaV1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown. Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling. These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics.
  
  
  
  Voltage-gated sodium channel NaV1.7 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 NaV1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV1.7 knockout mouse (NaV1.7Nav1.8) and selective small-molecule NaV1.7 antagonist PF-5198007. NaV1.7Nav1.8mice 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 NaV1.7Nav1.8and littermate controls. Loss, or blockade, of NaV1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV1.7 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 NaV1.8-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 NaV1.8-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 NaV1.7 alone in the viscera may be insufficient in targeting chronic visceral pain.
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK.
authors.forename: James R F
authors.initials: JR
authors.lastname: Hockley
authors.affiliation: Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: González-Cano
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK.
authors.forename: Sheridan
authors.identifier: 0000-0003-4469-6807
authors.initials: S
authors.lastname: McMurray
authors.affiliation: Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Tejada-Giraldez
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
authors.forename: Cian
authors.initials: C
authors.lastname: McGuire
authors.affiliation: Department of Biochemistry, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Wilbrey
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
authors.forename: Vincent
authors.identifier: 0000-0002-8483-0284
authors.initials: V
authors.lastname: Cibert-Goton
authors.affiliation: Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain.
authors.forename: Francisco R
authors.initials: FR
authors.lastname: Nieto
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pitcher
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Knowles
authors.affiliation: Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Baeyens
authors.affiliation: Molecular Nociception Group, Department of Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Winchester
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Bulmer
authors.affiliation: Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain.
authors.forename: Cruz Miguel
authors.initials: CM
authors.lastname: Cendán
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK.
authors.forename: Gordon
authors.identifier: 0000-0001-7033-8427
authors.initials: G
authors.lastname: McMurray
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002211:Capsaicin / Q000633:toxicity; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009149:Mustard Plant / Q000633:toxicity; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000172:deficiency* / Q000235:genetics; D059226:Nociceptive Pain / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D010938:Plant Oils / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D059265:Visceral Pain / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; D010938:Plant Oils; C503479:Scn9a protein, mouse; D026941:Sodium Channel Blockers; D002211:Capsaicin; C027793:mustard oil
keywords: NaV1.7; colorectal; heat pain; visceral nociception; visceral pain; voltage gated sodium channel