Selective spider toxins reveal a role for Na _v1.1 channel in mechanical pain

Abstract

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 _v1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Na _v1.1-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 _v1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Na _v1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain.