Selective spider toxins reveal a role for Na(v)1.1 channel in mechanical pain

Voltage-gated sodium (Na(v)) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Na(v) channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Na(v)1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Na(v)1.1-expressing fibers are modality-specific nociceptors: their activation elicits robust pain behaviors without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibers also express Na(v)1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Na(v)1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain.