Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice

Middleton, S. J. et al. (2022) Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice. Brain, 145(10), pp. 3637-3653. (doi: 10.1093/brain/awab482) (PMID:34957475) (PMCID:PMC9586547)

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Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.

Item Type:Articles
Additional Information:The project was supported by a strategic award from the Wellcome Trust (102645/Z/13/Z). D.L.B. is a Wellcome senior clinical scientist (202747/Z/16/Z). D.L.B. and S.J.M. acknowledge funding from the UK Medical Research Council (grant ref. MR/T020113/1). A.M.B. is a student in the OXION programme, also funded by the Wellcome Trust. M.L. acknowledges support from NIHR Cambridge Clinical Research Facility and NIHR Eastern Clinical Research. The project was supported by the Swedish Research Council (2015-02684), ALF Grants, Region Östergötlandand The Knut and Alice Wallenberg Foundation.
Glasgow Author(s) Enlighten ID:Weir, Dr Gregory
Authors: Middleton, S. J., Perini, I., Andreas C., T., Weir, G. A., McCann, K., Barry, A. M., Marshall, A., Lee, M., Mayo, L. M., Bohic, M., Baskozos, G., Morrison, I., Löken, L. S., McIntyre, S., Nagi, S. S., Staud, R., Sehlstedt, I., Johnson, R. D., Wessberg, J., Wood, J. N., Woods, C. G., Moqrich, A., Olausson, H., and Bennett, D. L.
College/School:College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Brain
Publisher:Oxford University Press
ISSN (Online):1460-2156
Published Online:27 December 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Brain 145(10): 3637-3653
Publisher Policy:Reproduced under a Creative Commons License

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