2. Academic Validation
  3. Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain

Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain

  • Nature. 2016 Jun 23;534(7608):494-9. doi: 10.1038/nature17976.
Jeremiah D Osteen 1,  Volker Herzig 2,  John Gilchrist 3,  Joshua J Emrick 1,  Chuchu Zhang 1,  Xidao Wang 4,  Joel Castro 5 6,  Sonia Garcia-Caraballo 5 6,  Luke Grundy 5 6,  Grigori Y Rychkov 6,  Andy D Weyer 7,  Zoltan Dekan 2,  Eivind A B Undheim 2,  Paul Alewood 2,  Cheryl L Stucky 7,  Stuart M Brierley 5 6,  Allan I Basbaum 4,  Frank Bosmans 3,  Glenn F King 2,  David Julius 1
Affiliations

Affiliations

  • 1 Department of Physiology, University of California, San Francisco, California 94143, USA.
  • 2 Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.
  • 3 Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
  • 4 Department of Anatomy, University of California, San Francisco, California 94143, USA.
  • 5 Visceral Pain Group, Flinders University, Bedford Park, Southern Australia, 5042, Australia.
  • 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.
  • 7 Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
PMID: 27281198 DOI: 10.1038/nature17976
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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