Journal Article

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

Herzig, Volker, Rychkov, Grigori Y., Dekan, Zoltan, Emrick, Joshua J., Castro, Joel, Stucky, Cheryl L., Grundy, Luke, Julius, David, Gilchrist, John, Wang, Xidao, Garcia-Caraballo, Sonia, Alewood, Paul, Undheim, Eivind A. B., Bosmans, Frank, Zhang, Chuchu, Basbaum, Allan I., Osteen, Jeremiah D., Weyer, Andy D., Brierley, Stuart M., King, Glenn F.

2016

Overview

Voltage-gated sodium (Na v ) 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 Na v 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 Na v 1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Na v 1.1-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 Na v 1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Na v 1.1 channels in regulating the excitability of sensory nerve fibres that mediate mechanical pain. Two spider toxins are shown to target the Na v 1.1 subtype of sodium channel specifically, shedding light on the role of these channels in mechanical pain signalling. Na v 1.1 channels mediate mechanical pain Mutations affecting several Na v 1 subtype voltage-gated sodium channels have been shown to be associated with insensitivity to pain or persistent pain syndromes. Na v 1.1 is expressed by somatosensory neurons, but no direct link has been established between this subtype and nociception. Further studies have been hampered by a paucity of pharmacological agents that discriminate between the closely related members of the Na v 1 family. Now David Julius and colleagues have identified two spider toxins specifically targeting Na v 1.1, and use them to show that this channel is key to the specific transduction of mechanical but not thermal pain by myelinated Aδ sensory fibres. Previous genetic studies of Na v 1.1 indicate that such selective agents may open therapeutic avenues in disorders associated with the central nervous system, such as epilepsy, autism and Alzheimer disease. The involvement of Na v 1.1 channels in mediating mechanical pain reported here was unexpected.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 14/63 / 631/378/1959/2605 / 631/378/2586 / 631/443/376 / 631/45/269/1152 / 64 / 64/60 / 82 / 82/51 / 82/81 / 9/74 / Animals / Disease Models, Animal / Female / Ganglia, Sensory - cytology / Humanities and Social Sciences / Hyperalgesia - chemically induced / Hyperalgesia - metabolism / Irritable Bowel Syndrome - metabolism / Male / multidisciplinary / Myelin Sheath - metabolism / NAV1.1 Voltage-Gated Sodium Channel - chemistry / NAV1.1 Voltage-Gated Sodium Channel - metabolism / Nerve Fibers - drug effects / Nerve Fibers - metabolism / Nociception - drug effects / Nociceptors / Nociceptors - drug effects / Nociceptors - metabolism / Oocytes - metabolism / Pain / Pain - chemically induced / Pain - metabolism / Physiological aspects / Protein Structure, Tertiary / Science / Sensory Receptor Cells - drug effects / Sensory Receptor Cells - metabolism / Sodium channels / Spider venoms / Spider Venoms - pharmacology / Spiders - chemistry / Stress, Mechanical / Substrate Specificity - drug effects / Temperature