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

2016; Nature Portfolio; Volume: 534; Issue: 7608 Linguagem: Inglês

10.1038/nature17976

1476-4687

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

Neurobiology and Insect Physiology Research

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. Two spider toxins are shown to target the Nav1.1 subtype of sodium channel specifically, shedding light on the role of these channels in mechanical pain signalling. Mutations affecting several Nav1 subtype voltage-gated sodium channels have been shown to be associated with insensitivity to pain or persistent pain syndromes. Nav1.1 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 Nav1 family. Now David Julius and colleagues have identified two spider toxins specifically targeting Nav1.1, 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 Nav1.1 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 Nav1.1 channels in mediating mechanical pain reported here was unexpected.