A mouse study shows that non-neuronal epidermal Merkel cells aid fine-touch perception in the skin through their expression of the Piezo2 mechanosensitive cation channel which then actively tunes the response to touch in adjacent somatosensory neurons. Merkel cells (also known as Merkel-Ranvier cells) are found in the vertebrate epidermis. They are non-neuronal but may make 'synapse-like' contact with neighbouring cells. It has been suggested that they are associated with the sensation of touch, but this has been difficult to prove and remains controversial. In this week's Nature two teams present clear evidence that Merkel cells are autonomous mechanosensors essential to fine touch perception. The cells express the mechanosensitive channel Piezo2, which allows them to actively tune somatosensory neurons' responses to touch. These results are consistent with a compound receptor system model in which epidermal cells help neurons to discriminate between different types of touch — such as flutter, stretch and pressure — and therefore to decode the fine details of objects. How we sense touch remains fundamentally unknown1,2. The Merkel cell–neurite complex is a gentle touch receptor in the skin that mediates slowly adapting responses of Aβ sensory fibres to encode fine details of objects3,4,5,6. This mechanoreceptor complex was recognized to have an essential role in sensing gentle touch nearly 50 years ago3,4. However, whether Merkel cells or afferent fibres themselves sense mechanical force is still debated, and the molecular mechanism of mechanotransduction is unknown1,2,7,8,9,10,11,12. Synapse-like junctions are observed between Merkel cells and associated afferents6,13,14,15, and yet it is unclear whether Merkel cells are inherently mechanosensitive or whether they can rapidly transmit such information to the neighbouring nerve1,2,16,17. Here we show that Merkel cells produce touch-sensitive currents in vitro. Piezo2, a mechanically activated cation channel, is expressed in Merkel cells. We engineered mice deficient in Piezo2 in the skin, but not in sensory neurons, and show that Merkel-cell mechanosensitivity completely depends on Piezo2. In these mice, slowly adapting responses in vivo mediated by the Merkel cell–neurite complex show reduced static firing rates, and moreover, the mice display moderately decreased behavioural responses to gentle touch. Our results indicate that Piezo2 is the Merkel-cell mechanotransduction channel and provide the first line of evidence that Piezo channels have a physiological role in mechanosensation in mammals. Furthermore, our data present evidence for a two-receptor-site model, in which both Merkel cells and innervating afferents act together as mechanosensors. The two-receptor system could provide this mechanoreceptor complex with a tuning mechanism to achieve highly sophisticated responses to a given mechanical stimulus15,18,19.

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.

The somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1) IB4⁺SNS-Cre/TdTomato⁺, 2) IB4⁻SNS-Cre/TdTomato⁺, and 3) Parv-Cre/TdTomato⁺ cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation.

The first point of our body’s contact with tactile stimuli (innocuous and noxious) is the epidermis, the outermost layer of skin that is largely composed of keratinocytes. Here, we sought to define the role that keratinocytes play in touch sensation in vivo and ex vivo. We show that optogenetic inhibition of keratinocytes decreases behavioral and cellular mechanosensitivity. These processes are inherently mediated by ATP signaling, as demonstrated by complementary cutaneous ATP release and degradation experiments. Specific deletion of P2X4 receptors in sensory neurons markedly decreases behavioral and primary afferent mechanical sensitivity, thus positioning keratinocyte-released ATP to sensory neuron P2X4 signaling as a critical component of baseline mammalian tactile sensation. These experiments lay a vital foundation for subsequent studies into the dysfunctional signaling that occurs in cutaneous pain and itch disorders, and ultimately, the development of novel topical therapeutics for these conditions.

Peripheral inflammation causes mechanical pain behavior and increased action potential firing. However, most studies examine inflammatory pain at acute, rather than chronic time points, despite chronic pain’s greater burden on patient populations, especially aged individuals. Furthermore, there is disagreement in the field about whether primary afferents contribute to chronic pain. Therefore, we sought to evaluate the contribution of nociceptor activity to the generation of pain behaviors during the acute and chronic phases of inflammation in both young and aged mice. We found that both young (2 months) and aged (> 18 months) mice exhibited prominent pain behaviors during both acute (2-day) and chronic (8-week) inflammation. However, young mice exhibited greater behavioral sensitization to mechanical stimuli than their aged counterparts. Teased fiber recordings in young animals revealed a 2-fold mechanical sensitization in C fibers during acute inflammation, but an unexpected 2-fold reduction in firing during chronic inflammation. Responsiveness to capsaicin and mechanical responsiveness of AM fibers were also reduced chronically. Importantly, this lack of sensitization in afferent firing during chronic inflammation occurred even as these inflamed mice exhibited continued behavioral sensitization. Interestingly, C fibers from inflamed aged animals showed no change in mechanical firing compared to controls during either the acute or chronic inflammatory phases, despite strong behavioral sensitization to mechanical stimuli at these time points. These results reveal two important findings: 1) nociceptor sensitization to mechanical stimulation depends on age and the chronicity of injury, and 2) maintenance of chronic inflammatory pain does not rely on enhanced peripheral drive. Significance Statement: Most peripheral pain research examines acute pain in young animals, with the assumption that peripheral pain mechanisms are similar during acute pain and chronic pain for animals of all ages. Our results indicate that peripheral nociceptors may contribute minimally to pain sensation at chronic inflammatory time points in young populations, and at either acute or chronic time points in aged populations. These findings have important implications for novel analgesic design, as drugs targeting peripheral pain mechanisms observed under acute inflammatory conditions may be unlikely to show efficacy under chronic inflammatory conditions. Additionally, since nociceptors from aged animals do not change their firing rates in response to acute or chronic pain, peripherally-acting analgesics may also be largely ineffective in aged populations.

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate.