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_v1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Na_v1.1-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_v1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Na_v1.1 channels in regulating the excitability of sensory nerve fibres that mediate 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.

Disulfide-rich peptides are the dominant component of most animal venoms. These peptides have received much attention as leads for the development of novel therapeutic agents and bioinsecticides because they target a wide range of neuronal receptors and ion channels with a high degree of potency and selectivity. In addition, their rigid disulfide framework makes them particularly well suited for addressing the crucial issue of in vivo stability. Structural and functional characterization of these peptides necessitates the development of a robust, reliable expression system that maintains their native disulfide framework. The bacterium Escherichia coli has long been used for economical production of recombinant proteins. However, the expression of functional disulfide-rich proteins in the reducing environment of the E. coli cytoplasm presents a significant challenge. Thus, we present here an optimised protocol for the expression of disulfide-rich venom peptides in the periplasm of E. coli , which is where the endogenous machinery for production of disulfide-bonds is located. The parameters that have been investigated include choice of media, induction conditions, lysis methods, methods of fusion protein and peptide purification, and sample preparation for NMR studies. After each section a recommendation is made for conditions to use. We demonstrate the use of this method for the production of venom peptides ranging in size from 2 to 8 kDa and containing 2–6 disulfide bonds.

From offense to defense: Venom in snakes is largely used to subdue and/or kill prey, and most venoms have clear actions that facilitate death or paralysis. In one group of snakes, however, venom has evolved and shifted from predation to protection. Specifically, in three different lineages of “spitting” snakes, venom is used to deter predators. Kazandjian et al. show that similar adaptions have occurred within these lineages that transform cytotoxic components into a mixture that acts on mammalian sensory neurons and causes pain. The authors argue that increased predation on these lineages led to similar shifts in venom function. Science , this issue p. 386

Significance: The economic burden of chronic pain in the United States is currently ∼$600 billion per annum, which exceeds the combined annual cost of cancer, heart disease, and diabetes. Few drugs are available for treating chronic pain, and many have limited efficacy and dose-limiting side-effects. Humans with inheritable loss-of-function mutations in the voltage-gated sodium channel Na _V 1.7 are indifferent to all types of pain, and therefore drugs that block this channel should be useful analgesics for treating many pain conditions. Herein we describe Ssm6a, a peptide from centipede venom that potently and selectively blocks the human Na _V 1.7 channel. Ssm6a proved to be more analgesic than morphine in rodent pain models and did not cause any side-effects.