Progressive recruitment of distal MEC-4 channels determines touch response strength in C. elegans.

Touch deforms, or strains, the skin beyond the immediate point of contact. The spatiotemporal nature of the touch-induced strain fields depend on the mechanical properties of the skin and the tissues below. Somatosensory neurons that sense touch branch out within the skin and rely on a set of mechano-electrical transduction channels distributed within their dendrites to detect mechanical stimuli. Here, we sought to understand how tissue mechanics shape touch-induced mechanical strain across the skin over time and how individual channels located in different regions of the strain field contribute to the overall touch response. We leveraged Caenorhabditis elegans' touch receptor neurons as a simple model amenable to in vivo whole-cell patch-clamp recording and an integrated experimental-computational approach to dissect the mechanisms underlying the spatial and temporal dynamics we observed. Consistent with the idea that strain is produced at a distance, we show that delivering strong stimuli outside the anatomical extent of the neuron is sufficient to evoke MRCs. The amplitude and kinetics of the MRCs depended on both stimulus displacement and speed. Finally, we found that the main factor responsible for touch sensitivity is the recruitment of progressively more distant channels by stronger stimuli, rather than modulation of channel open probability. This principle may generalize to somatosensory neurons with more complex morphologies.

Somatosensory neurons integrate the geometry of skin deformation and mechanotransduction channels to shape touch sensing.

Touch sensation hinges on force transfer across the skin and activation of mechanosensitive ion channels along the somatosensory neurons that invade the skin. This skin-nerve sensory system demands a quantitative model that spans the application of mechanical loads to channel activation. Unlike prior models of the dynamic responses of touch receptor neurons in Caenorhabditis elegans (Eastwood et al., 2015), which substituted a single effective channel for the ensemble along the TRNs, this study integrates body mechanics and the spatial recruitment of the various channels. We demonstrate that this model captures mechanical properties of the worm's body and accurately reproduces neural responses to simple stimuli. It also captures responses to complex stimuli featuring non-trivial spatial patterns, like extended or multiple contacts that could not be addressed otherwise. We illustrate the importance of these effects with new experiments revealing that skin-neuron composites respond to pre-indentation with increased currents rather than adapting to persistent stimulation.

Feeling force: physical and physiological principles enabling sensory mechanotransduction.

Organisms as diverse as microbes, roundworms, insects, and mammals detect and respond to applied force. In animals, this ability depends on ionotropic force receptors, known as mechanoelectrical transduction (MeT) channels, that are expressed by specialized mechanoreceptor cells embedded in diverse tissues and distributed throughout the body. These cells mediate hearing, touch, and proprioception and play a crucial role in regulating organ function. Here, we attempt to integrate knowledge about the architecture of mechanoreceptor cells and their sensory organs with principles of cell mechanics, and we consider how engulfing tissues contribute to mechanical filtering. We address progress in the quest to identify the proteins that form MeT channels and to understand how these channels are gated. For clarity and convenience, we focus on sensory mechanobiology in nematodes, fruit flies, and mice. These themes are emphasized: asymmetric responses to applied forces, which may reflect anisotropy of the structure and mechanics of sensory mechanoreceptor cells, and proteins that function as MeT channels, which appear to have emerged many times through evolution.

A 'toothache tree' alkylamide inhibits Aδ mechanonociceptors to alleviate mechanical pain.

In traditional medicine, the 'toothache tree' and other plants of the Zanthoxylum genus have been used to treat inflammatory pain conditions, such as toothache and rheumatoid arthritis. Here we examined the cellular and molecular mechanisms underlying the analgesic properties of hydroxy-α-sanshool, the active alkylamide produced by Zanthoxylum plants. Consistent with its analgesic effects in humans, sanshool treatment in mice caused a selective attenuation of mechanical sensitivity under naïve and inflammatory conditions, with no effect on thermal sensitivity. To elucidate the molecular mechanisms by which sanshool attenuates mechanical pain, we performed single fibre recordings, calcium imaging and whole-cell electrophysiology of cultured sensory neurons. We found that: (1) sanshool potently inhibits Aδ mechanonociceptors that mediate both sharp acute pain and inflammatory pain; (2) sanshool inhibits action potential firing by blocking voltage-gated sodium currents in a subset of somatosensory neurons, which express a unique combination of voltage-gated sodium channels; and (3) heterologously expressed Nav1.7 is most strongly inhibited by sanshool as compared to other sodium channels expressed in sensory neurons. These results suggest that sanshool targets voltage-gated sodium channels on Aδ mechanosensory nociceptors to dampen excitability and thus induce 'fast pain' analgesia.