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Itch triggers scratching, a behavioural defence mechanism that aids in the removal of harmful irritants and parasites 1 . Chemical itch is triggered by many endogenous and exogenous cues, such as pro-inflammatory histamine, which is released during an allergic reaction 1 . Mechanical itch can be triggered by light sensations such as wool fibres or a crawling insect 2 . In contrast to chemical itch pathways, which have been extensively studied, the mechanisms that underlie the transduction of mechanical itch are largely unknown. Here we show that the mechanically activated ion channel PIEZO1 (ref. 3 ) is selectively expressed by itch-specific sensory neurons and is required for their mechanically activated currents. Loss of PIEZO1 function in peripheral neurons greatly reduces mechanically evoked scratching behaviours and both acute and chronic itch-evoked sensitization. Finally, mice expressing a gain-of-function Piezo1 allele 4 exhibit enhanced mechanical itch behaviours. Our studies reveal the polymodal nature of itch sensory neurons and identify a role for PIEZO1 in the sensation of itch. Experiments in mice show that the mechanically activated ion channel PIEZO1 is expressed in itch-specific sensory neurons and has a role in transducing mechanical itch.

Steroids regulate cell proliferation, tissue development, and cell signaling via two pathways: a nuclear receptor mechanism and genome-independent signaling. Sperm activation, egg maturation, and steroid-induced anesthesia are executed via the latter pathway, the key components of which remain unknown. Here, we present characterization of the human sperm progesterone receptor that is conveyed by the orphan enzyme α/β hydrolase domain–containng protein 2 (ABHD2). We show that ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane. The 2AG inhibits the sperm calcium channel (CatSper), and its removal leads to calcium influx via CatSper and ensures sperm activation. This study reveals that progesterone-activated endocannabinoid depletion by ABHD2 is a general mechanism by which progesterone exerts its genome-independent action and primes sperm for fertilization.

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch. Chronic itch is a debilitating disorder that can last for months or years. Eczema, or atopic dermatitis, is the most common cause for chronic itch, affecting one in ten people worldwide. Many treatments for the condition are ineffective, and the exact cause of the disease is unknown, but many different types of cells are likely involved. These include skin cells and inflammation-promoting immune cells, as well as nerve cells that detect inflammation, relay itch and pain information to the brain, and regulate the immune system. Learning more about how these cells interact in eczema may help scientists find better treatments for the condition. So far, a lot of research has focused on static ‘snapshots’ of mature eczema lesions from human skin or animal models. These studies have identified abnormalities in genes or cells, but have not revealed how these genes and cells interact over time to cause chronic itch and inflammation. Now, Walsh et al. reveal that immune cells called neutrophils trigger chronic itch in eczema. The experiments involved mice with a condition that mimics eczema, and showed that removing the neutrophils in these mice alleviated their itching. They also showed that dramatic and rapid changes occur in the nervous system of mice suffering from the eczema-like condition. For example, excess nerves grow in the animals’ damaged skin, genes in the nerves that detect sensations become hyperactive, and changes occur in the spinal cord that have been linked to nerve pain. When neutrophils are absent, these changes do not take place. These findings show that neutrophils play a key role in chronic itch and inflammation in eczema. Drugs that target neutrophils, which are already used to treat other diseases, might help with chronic itch, but they would need to be tested before they can be used on people with eczema.

Sphingosine-1-phosphate (S1P) plays important roles as a signaling lipid in a variety of physiological and pathophysiological processes. S1P signals via a family of G-protein-coupled receptors (GPCRs) (S1P 1–5 ) and intracellular targets. Here, we report on photoswitchable analogs of S1P and its precursor sphingosine, respectively termed PhotoS1P and PhotoSph. PhotoS1P enables optical control of S1P 1–3 , shown through electrophysiology and Ca 2+ mobilization assays. We evaluated PhotoS1P in vivo, where it reversibly controlled S1P 3 -dependent pain hypersensitivity in mice. The hypersensitivity induced by PhotoS1P is comparable to that induced by S1P. PhotoS1P is uniquely suited for the study of S1P biology in cultured cells and in vivo because it exhibits prolonged metabolic stability compared to the rapidly metabolized S1P. Using lipid mass spectrometry analysis, we constructed a metabolic map of PhotoS1P and PhotoSph. The formation of these photoswitchable lipids was found to be light dependent, providing a novel approach to optically probe sphingolipid biology. A photoswitchable analog of spingosine-1-phosphate (S1P) that allows for modulation of the action of this bioactive lipid exhibits prolonged metabolic stability compared to S1P, activates S1P receptors in cells and mediates nociception in mice.

Of the various temperature-sensitive ion channels identified previously, three have now been found to act in concert to detect painful heat and initiate protective reflexes. Of the various temperature-sensitive ion channels identified previously, three have now been found to act in concert to detect painful heat and initiate protective reflexes.

Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds.

Of the various temperature-sensitive ion channels identified previously, three have now been found to act in concert to detect painful heat and initiate protective reflexes.