Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain.
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.
Department of Physiology, University of California, San Francisco, California 94143, USA.
Jeremiah D
JD
Osteen
Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.
Volker
V
Herzig
Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
John
J
Gilchrist
Department of Physiology, University of California, San Francisco, California 94143, USA.
Joshua J
JJ
Emrick
Department of Physiology, University of California, San Francisco, California 94143, USA.
Chuchu
C
Zhang
Department of Anatomy, University of California, San Francisco, California 94143, USA.
Xidao
X
Wang
Visceral Pain Group, Flinders University, Bedford Park, Southern Australia, 5042, Australia.|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
J
Castro
Visceral Pain Group, Flinders University, Bedford Park, Southern Australia, 5042, Australia.|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.
Sonia
S
Garcia-Caraballo
Visceral Pain Group, Flinders University, Bedford Park, Southern Australia, 5042, Australia.|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.
Luke
L
Grundy
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.
Grigori Y
GY
Rychkov
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Andy D
AD
Weyer
Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.
Zoltan
Z
Dekan
Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.
Eivind A B
EA
Undheim
Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.
Paul
P
Alewood
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Cheryl L
CL
Stucky
Visceral Pain Group, Flinders University, Bedford Park, Southern Australia, 5042, Australia.|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.
Stuart M
SM
Brierley
Department of Anatomy, University of California, San Francisco, California 94143, USA.
Allan I
AI
Basbaum
Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Frank
F
Bosmans
Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.
Glenn F
GF
King
Department of Physiology, University of California, San Francisco, California 94143, USA.
David
D
Julius
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D017950:Ganglia, Sensory / Q000166:cytology; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism; D043183:Irritable Bowel Syndrome / Q000378:metabolism; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000378:metabolism*; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism; D059225:Nociception / Q000187:drug effects*; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology*; D013112:Spiders / Q000737:chemistry; D013314:Stress, Mechanical; D013379:Substrate Specificity / Q000187:drug effects; D013696:Temperature
D062550:NAV1.1 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse; D013111:Spider Venoms