Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons

The peripheral terminals of primary sensory neurons detect histamine and non-histamine itch-provoking ligands through molecularly distinct transduction mechanisms. It remains unclear, however, whether these distinct pruritogens activate the same or different afferent fibers. We utilized a strategy of reversibly silencing specific subsets of murine pruritogen-sensitive sensory axons by targeted delivery of a charged sodium-channel blocker and found that functional blockade of histamine itch did not affect the itch evoked by chloroquine or SLIGRL-NH2, and vice versa. Notably, blocking itch-generating fibers did not reduce pain-associated behavior. However, silencing TRPV1+ or TRPA1+ neurons allowed AITC or capsaicin respectively to evoke itch, implying that certain peripheral afferents may normally indirectly inhibit algogens from eliciting itch. These findings support the presence of functionally distinct sets of itch-generating neurons and suggest that targeted silencing of activated sensory fibers may represent a clinically useful anti-pruritic therapeutic approach for histaminergic and non-histaminergic pruritus

Photochemical activation of TRPA1 channels in neurons and animals

Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild type animals. Surprisingly, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in non-transgenic animals, including humans

Bortezomib-induced neuropathy is in part mediated by the sensitization of TRPV1 channels

Abstract TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin nerve terminals. Tissue injury and inflammation result in the sensitization of TRPV1 and sustained activation of TRPV1 can lead to cellular toxicity though calcium influx. To identify signals that trigger TRPV1 sensitization after a 24-h exposure, we developed a phenotypic assay in mouse primary sensory neurons and performed an unbiased screen with a compound library of 480 diverse bioactive compounds. Chemotherapeutic agents, calcium ion deregulators and protein synthesis inhibitors were long-acting TRPV1 sensitizers. Amongst the strongest TRPV1 sensitizers were proteasome inhibitors, a class that includes bortezomib, a chemotherapeutic agent that causes small fiber neuropathy in 30–50% of patients. Prolonged exposure of bortezomib produced a TRPV1 sensitization that lasted several days and neurite retraction in vitro and histological and behavioral changes in male mice in vivo. TRPV1 knockout mice were protected from epidermal nerve fiber loss and a loss of sensory discrimination after bortezomib treatment. We conclude that long-term TRPV1 sensitization contributes to the development of bortezomib-induced neuropathy and the consequent loss of sensation, major deficits experienced by patients under this chemotherapeutic agent