Voltage-gated sodium (Nav) 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 Nav 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 Nav1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Nav1.1-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 Nav1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Nav1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain.

Venoms are one of the most convergent of animal traits known, and encompass a much greater taxonomic and functional diversity than is commonly appreciated. This knowledge gap limits the potential of venom as a model trait in evolutionary biology. Here, we summarize the taxonomic and functional diversity of animal venoms and relate this to what is known about venom system morphology, venom modulation, and venom pharmacology, with the aim of drawing attention to the importance of these largely neglected aspects of venom research. We find that animals have evolved venoms at least 101 independent times and that venoms play at least 11 distinct ecological roles in addition to predation, defense, and feeding. Comparisons of different venom systems suggest that morphology strongly influences how venoms achieve these functions, and hence is an important consideration for understanding the molecular evolution of venoms and their toxins. Our findings also highlight the need for more holistic studies of venom systems and the toxins they contain. Greater knowledge of behavior, morphology, and ecologically relevant toxin pharmacology will improve our understanding of the evolution of venoms and their toxins, and likely facilitate exploration of their potential as sources of molecular tools and therapeutic and agrochemical lead compounds.

Despite the staggering diversity of venomous animals, there seems to be remarkable convergence in regard to the types of proteins used as toxin scaffolds. However, our understanding of this fascinating area of evolution has been hampered by the narrow taxonomical range studied, with entire groups of venomous animals remaining almost completely unstudied. One such group is centipedes, class Chilopoda, which emerged about 440 Ma and may represent the oldest terrestrial venomous lineage next to scorpions. Here, we provide the first comprehensive insight into the chilopod "venome" and its evolution, which has revealed novel and convergent toxin recruitments as well as entirely new toxin families among both high- and low molecular weight venom components. The ancient evolutionary history of centipedes is also apparent from the differences between the Scolopendromorpha and Scutigeromorpha venoms, which diverged over 430 Ma, and appear to employ substantially different venom strategies. The presence of a wide range of novel proteins and peptides in centipede venoms highlights these animals as a rich source of novel bioactive molecules. Understanding the evolutionary processes behind these ancient venom systems will not only broaden our understanding of which traits make proteins and peptides amenable to neofunctionalization but it may also aid in directing bioprospecting efforts.