Abstract

Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibres of the pain pathway. Local anaesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes of these channels and their contributions to chemical, mechanical, or thermal pain. Here we identify and characterize spider (Heteroscodra maculata) toxins that selectively activate the Nav1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Nav1.1-expressing fibres are modality-specific nociceptors: their activation elicits robust pain behaviours without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibres also express Nav1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Nav1.1 channels in regulating the excitability of sensory nerve fibres that mediate mechanical pain.

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Accessions

Data deposits

Sequences and activity profiles for Hm1a and Hm1b can be found in the ArachnoServer database49 under accession numbers AS000224 and AS002363, respectively.

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Acknowledgements

We thank the Deutsche Arachnologische Gesellschaft and particularly I. Wendt, J. Broghammer, A. Schlosser, B. Rast, M. Luescher, C. and F. Schneider and H. Auer for providing arthropods for milking; W. Catterall for providing floxed Nav1.1 mice; and J. Poblete, J. Maddern, T. O’Donnell and A. Harrington for technical assistance. This work was supported by a T32 Postdoctoral Training Grant from the UCSF CVRI (J.D.O.), Ruth Kirschstein NIH postdoctoral (F32NS081907 to J.D.O.) and predoctoral (F31NS084646 to J.G. and F30DE023476 to J.J.E.) fellowships, the National Institutes of Health (R37NS065071 and R01NS081115 to D.J., R01NS091352 to F.B., R01NS040538 and R01NS070711 to C.L.S., and R37NS014627 and R01DA29204 to A.I.B.), the National Health and Medical Research Council of Australia (Project Grant APP1083480 to S.M.B., Program Grant APP1072113 and Principal Research Fellowship APP1044414 to G.F.K.), and a grant from the Wellcome Trust to A.I.B. S.M.B. is a NHMRC R.D Wright Biomedical Research Fellow.

Author information

Affiliations

  1. Department of Physiology, University of California, San Francisco, California 94143, USA

    • Jeremiah D. Osteen
    • , Joshua J. Emrick
    • , Chuchu Zhang
    •  & David Julius
  2. Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia

    • Volker Herzig
    • , Zoltan Dekan
    • , Eivind A. B. Undheim
    • , Paul Alewood
    •  & Glenn F. King
  3. Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • John Gilchrist
    •  & Frank Bosmans
  4. Department of Anatomy, University of California, San Francisco, California 94143, USA

    • Xidao Wang
    •  & Allan I. Basbaum
  5. Visceral Pain Group, Flinders University, Bedford Park, Southern Australia, 5042, Australia

    • Joel Castro
    • , Sonia Garcia-Caraballo
    • , Luke Grundy
    •  & Stuart M. Brierley
  6. Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, Southern Australia 5000, Australia

    • Joel Castro
    • , Sonia Garcia-Caraballo
    • , Luke Grundy
    • , Grigori Y. Rychkov
    •  & Stuart M. Brierley
  7. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA

    • Andy D. Weyer
    •  & Cheryl L. Stucky

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Contributions

J.D.O., V.H., E.A.B.U., G.F.K. and D.J. carried out venom collection and screening, toxin purification and characterization. Z.D. and P.A. carried out Hm1a synthesis. J.D.O., J.G., C.Z., D.J. and F.B. designed, performed, and analysed electrophysiological and calcium imaging experiments to determine toxin mechanism and selectivity. J.J.E., J.D.O., X.W. A.I.B, and D.J. designed, performed and analysed histological experiments. A.D.W. and C.L.S. designed, performed, and analysed skin-nerve recordings. X.W., J.D.O., D.J., and A.I.B. designed, performed, and analysed behavioural experiments to assess somatic function. J.C., S.G.-C., L.G., G.Y.R. and S.M.B. designed, performed and analysed studies relating to colonic afferent and patch clamp pharmacological studies. All authors contributed to the discussion and interpretation of the results. J.D.O. and D.J. wrote the manuscript with contributions and suggestions from all authors.

Competing interests

The authors’ institutions have submitted provisional patent applications based, in part, on the work described in this article.

Corresponding authors

Correspondence to Frank Bosmans or Glenn F. King or David Julius.

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    Supplementary Table

    This file contains Supplementary Table 1, a list of venoms that produced no detectible or specific calcium response in cultured sensory neurons.

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https://doi.org/10.1038/nature17976

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