Topical Oxaliplatin Produces Gain- and Loss-of-Function in Multiple Classes of Sensory Afferents.

The platinum chemotherapeutic oxaliplatin produces dose-limiting pain, dysesthesia, and cold hypersensitivity in most patients immediately after infusion. An improved understanding of the mechanisms underlying these symptoms is urgently required to facilitate the development of symptomatic or preventative therapies. In this study, we have used skin-saphenous nerve recordings in vitro and behavioral experiments in mice to characterize the direct effects of oxaliplatin on different types of sensory afferent fibers.

Pain-causing stinging nettle toxins target TMEM233 to modulate Na1.7 function.

Voltage-gated sodium (Na) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived Na channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at Na channels, and that co-expression of TMEM233 modulates the gating properties of Na1.

Passive transfer of fibromyalgia symptoms from patients to mice.

Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons.

Australian funnel-web spiders evolved human-lethal δ-hexatoxins for defense against vertebrate predators.

Australian funnel-web spiders are infamous for causing human fatalities, which are induced by venom peptides known as δ-hexatoxins (δ-HXTXs). Humans and other primates did not feature in the prey or predator spectrum during evolution of these spiders, and consequently the primate lethality of δ-HXTXs remains enigmatic. Funnel-web envenomations are mostly inflicted by male spiders that wander from their burrow in search of females during the mating season, which suggests a role for δ-HXTXs in self-defense since male spiders rarely feed during this period.

Neurotoxic peptides from the venom of the giant Australian stinging tree.

Stinging trees from Australasia produce remarkably persistent and painful stings upon contact of their stiff epidermal hairs, called trichomes, with mammalian skin. -induced acute pain typically lasts for several hours, and intermittent painful flares can persist for days and weeks. Pharmacological activity has been attributed to small-molecule neurotransmitters and inflammatory mediators, but these compounds alone cannot explain the observed sensory effects.

Characterization of Synthetic Tf2 as a Na1.3 Selective Pharmacological Probe.

Na1.3 is a subtype of the voltage-gated sodium channel family. It has been implicated in the pathogenesis of neuropathic pain, although the contribution of this channel to neuronal excitability is not well understood.

Animal toxins - Nature's evolutionary-refined toolkit for basic research and drug discovery.

Venomous animals have evolved toxins that interfere with specific components of their victim's core physiological systems, thereby causing biological dysfunction that aids in prey capture, defense against predators, or other roles such as intraspecific competition. Many animal lineages evolved venom systems independently, highlighting the success of this strategy. Over the course of evolution, toxins with exceptional specificity and high potency for their intended molecular targets have prevailed, making venoms an invaluable and almost inexhaustible source of bioactive molecules, some of which have found use as pharmacological tools, human therapeutics, and bioinsecticides.

Manipulation of a spider peptide toxin alters its affinity for lipid bilayers and potency and selectivity for voltage-gated sodium channel subtype 1.7.

Huwentoxin-IV (HwTx-IV) is a gating modifier peptide toxin from spiders that has weak affinity for the lipid bilayer. As some gating modifier toxins have affinity for model lipid bilayers, a tripartite relationship among gating modifier toxins, voltage-gated ion channels, and the lipid membrane surrounding the channels has been proposed. We previously designed an HwTx-IV analogue (gHwTx-IV) with reduced negative charge and increased hydrophobic surface profile, which displays increased lipid bilayer affinity and activity at the voltage-gated sodium channel subtype 1.

Na 1.6 regulates excitability of mechanosensitive sensory neurons.

Key Points: Voltage-gated sodium channels are critical for peripheral sensory neuron transduction and have been implicated in a number of painful and painless disorders. The β-scorpion toxin, Cn2, is selective for Na 1.6 in dorsal root ganglion neurons.

Toxins as tools: Fingerprinting neuronal pharmacology.

Toxins have been used as tools for decades to study the structure and function of neuronal ion channels and receptors. The biological origin of these toxins varies from single cell organisms, including bacteria and algae, to complex multicellular organisms, including a wide variety of plants and venomous animals. Toxins are a structurally and functionally diverse group of compounds that often modulate neuronal function by interacting with an ion channel or receptor.

The E15R Point Mutation in Scorpion Toxin Cn2 Uncouples Its Depressant and Excitatory Activities on Human Na1.6.

We report the chemical synthesis of scorpion toxin Cn2, a potent and highly selective activator of the human voltage-gated sodium channel Na1.6. In an attempt to decouple channel activation from channel binding, we also synthesized the first analogue of this toxin, Cn2[E15R].

Sodium Channels and Venom Peptide Pharmacology.

Venomous animals including cone snails, spiders, scorpions, anemones, and snakes have evolved a myriad of components in their venoms that target the opening and/or closing of voltage-gated sodium channels to cause devastating effects on the neuromuscular systems of predators and prey. These venom peptides, through design and serendipity, have not only contributed significantly to our understanding of sodium channel pharmacology and structure, but they also represent some of the most phyla- and isoform-selective molecules that are useful as valuable tool compounds and drug leads. Here, we review our understanding of the basic function of mammalian voltage-gated sodium channel isoforms as well as the pharmacology of venom peptides that act at these key transmembrane proteins.

The pharmacology of voltage-gated sodium channel activators.

Toxins and venom components that target voltage-gated sodium (Na) channels have evolved numerous times due to the importance of this class of ion channels in the normal physiological function of peripheral and central neurons as well as cardiac and skeletal muscle. Na channel activators in particular have been isolated from the venom of spiders, wasps, snakes, scorpions, cone snails and sea anemone and are also produced by plants, bacteria and algae. These compounds have provided key insight into the molecular structure, function and pathophysiological roles of Na channels and are important tools due to their at times exquisite subtype-selectivity.

Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1.

Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (Na), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on Na1.1-1.

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails.

Some venomous cone snails feed on small fishes using an immobilizing combination of synergistic venom peptides that target Kv and Nav channels. As part of this envenomation strategy, δ-conotoxins are potent ichtyotoxins that enhance Nav channel function. δ-Conotoxins belong to an ancient and widely distributed gene superfamily, but any evolutionary link from ancestral worm-eating cone snails to modern piscivorous species has not been elucidated.