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.

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.

The sense of touch hinges on tissues transducing stimuli applied to the skin and somatosensory neurons converting mechanical inputs into currents. Like mammalian Pacinian corpuscles, the light-touch response of the prime model organism C. elegans adapts rapidly, and is symmetrically activated by the onset and offset of a step indentation. Here, we propose a quantitative model that combines transduction of stimuli across the skin and subsequent gating of mechanoelectrical channels. For mechanics, we use an elastic model based on geometrically-nonlinear deformations of a pressurized cylindrical shell. For gating, we build upon consequences of the dermal layer’s thinness and tangential stimuli. Our model demonstrates how the onset-offset symmetry arises from the coupling of mechanics and adaptation, and accounts for experimental neural responses to a broad variety of stimuli. Predicted effects of modifications in the mechanics or the internal pressure of the body are tested against mechanical and neurophysiological experiments.

Mechanosensitive DEG/ENaC/ASIC channels in C. elegans touch receptor neurons (TRNs) respond at the onset and offset of a stimulus. The rapidly adapting and nearly symmetric mechanoreceptor currents (MRCs) in TRNs resemble those believed to underpin receptor potentials in mammalian Pacinian corpuscles. Though TRN anatomy differs from that of Pacinian corpuscles, the TRNs, like other touch-sensitive somatosensory neurons, are embedded in the animal's skin and rely on that skin to filter and transfer mechanical stress. The C. elegans TRNs provide a system in which we not only know the identity of the mechano-electrical transduction channel and many of its interacting partners, but can also explore how MRCs are shaped by the mechanical microenvironment and surrounding tissues. We use in vivo whole-cell patch-clamp in combination with a piezoelectric stack-based stimulator and photodiode-based motion detector (Peng et al., Neuron, 2013) to probe this system at high (2.5kHz) bandwidth. Consistent with prior work, we find that MRC amplitude increases with displacement and decreases with distance from the cell body. The amplitude and kinetics of MRCs increase with stimulus rate, saturating above a speed of 6mm/s. With sinusoidal stimuli, we confirm that MRC activation is frequency dependent. Lastly, we find that MRCs adapt both to a constant pre-indentation and during continuous sinusoidal stimuli. We are developing a model that integrates the biomechanics of the worm body, the distribution of DEG/ENaC/ASIC channels, and the channels' dependence on both stimulus indentation and velocity to understand these biophysical phenomena. We hope this model will guide genetic dissection of the molecular basis of frequency dependence and both time- and indentation-dependent adaptation. Work was supported by F31NS093825 to SK and R01NS047715 to MBG. We thank A. Ricci and A. Peng for assistance in building the stimulator/photodiode motion detector.

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.

Key points Extracts from the toothache tree (Zanthoxylum) are used to treat inflammatory pain, such as toothache and arthritis. Hydroxy‐α‐sanshool (sanshool) is a major alkylamide in extracts from Zanthoxylum plants. Sanshool treatment in mice caused a selective attenuation of mechanical sensitivity under naïve and inflammatory conditions Sanshool inhibits Aδ mechanonociceptors that mediate both sharp acute pain and inflammatory pain, and inhibits the activity of multiple voltage‐gated sodium channel subtypes, among which Nav1.7 is the most strongly affected. Our data implicate Nav1.7 as a key mediator of inflammatory mechanical pain in ‘fast pain’ mechanosensory neurons. Abstract 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.

Many native cultures use extracts from Xanthozylum plants to topically treat toothache and joint pain. One active component of these extracts is the alkylamide, hydroxy-α-sanshool, which induces tingling and numbing paresthesia when applied to the skin or tongue. To understand the physiological mechanisms underlying paresthesias, we sought to identify the molecular targets of sanshool in the somatosensory system. We first measured the analgesic properties of sanshool using mouse models of somatosensory behavior. Topical application of sanshool on the hind paw of naïve mice did not alter their sensitivity to noxious thermal or mechanical stimuli. However, in a model of neurogenic inflammation, sanshool acutely suppressed inflammatory hypersensitivity to mechanical force whereas it did not suppress hypersensitivity to heat. These data suggest that sanshool inhibits activity of a subset of sensory neurons that transduce mechanical, but not thermal, stimuli. In cultured dorsal root ganglion (DRG) neurons from mice, sanshool inhibited action potential (AP) firing in a subset of medium-to-large diameter neurons, which are thought to mediate mechanotransduction. In contrast, sanshool did not inhibit AP firing in small-diameter sensory neurons, which predominantly transduce noxious heat. In addition to size, sensory neurons are distinct in their expression of sensory neuron-specific voltage-gated sodium channels. Thus the differential effect of sanshool on sensory neurons may be due to selective activity of sanshool on different sodium channels. To test this idea, we compared the effects of sanshool on two sodium channel subtypes that are expressed in sensory neurons, Nav1.7 and 1.8. Sanshool reduced the magnitude of Nav1.7 and Nav1.8 currents but caused a hyperpolarizing shift in the steady-state inactivation curve of Nav1.7 only. Thus intrinsic molecular differences between sensory neurons, such as expression of different sodium channel subtypes, may underlie specificity of sanshool action.