Visceral and somatic pain modalities reveal Na V 1.7-independent visceral nociceptive pathways.

Autor: Hockley JR; Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK., González-Cano R; Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain., McMurray S; Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK., Tejada-Giraldez MA; Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain., McGuire C; 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., Torres A; Department of Biochemistry, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain., Wilbrey AL; Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK., Cibert-Goton V; 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., Nieto FR; Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain., Pitcher T; Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK., Knowles CH; 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., Baeyens JM; Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain., Wood JN; Molecular Nociception Group, Department of Biology, University College London, Gower Street, London, WC1E 6BT, UK., Winchester WJ; Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK., Bulmer DC; 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., Cendán CM; Department of Pharmacology, Biomedical Research Centre (CIBM) and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain., McMurray G; Neuroscience and Pain Research Unit, Pfizer Ltd., The Portway Building, Granta Science Park, Cambridge, CB21 6GS, UK.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2017 Apr 15; Vol. 595 (8), pp. 2661-2679. Date of Electronic Publication: 2017 Mar 01.
DOI: 10.1113/JP272837
Abstrakt: Key Points: Voltage-gated sodium channels play a fundamental role in determining neuronal excitability. Specifically, voltage-gated sodium channel subtype Na V 1.7 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 Na V 1.7 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.
Abstract: 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.
(© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)
Databáze: MEDLINE
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