Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature 2016 Jun 23;534(7608):494-9
Date
06/10/2016Pubmed ID
27281198Pubmed Central ID
PMC4919188DOI
10.1038/nature17976Scopus ID
2-s2.0-84975781988 (requires institutional sign-in at Scopus site) 220 CitationsAbstract
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.
Author List
Osteen JD, Herzig V, Gilchrist J, Emrick JJ, Zhang C, Wang X, Castro J, Garcia-Caraballo S, Grundy L, Rychkov GY, Weyer AD, Dekan Z, Undheim EA, Alewood P, Stucky CL, Brierley SM, Basbaum AI, Bosmans F, King GF, Julius DAuthor
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDisease Models, Animal
Female
Ganglia, Sensory
Hyperalgesia
Irritable Bowel Syndrome
Male
Myelin Sheath
NAV1.1 Voltage-Gated Sodium Channel
Nerve Fibers
Nociception
Nociceptors
Oocytes
Pain
Protein Structure, Tertiary
Sensory Receptor Cells
Spider Venoms
Spiders
Stress, Mechanical
Substrate Specificity
Temperature