The exciting novel breakthrough by Hill and colleagues enhances our understanding of peripheral mechanical itch transduction mechanisms especially in CP states. These nerve fibers are also sensitive to histaminergic and non-histaminergic chemical pruritogens, contrary to the previously described PIEZO2 channels, which are solely responsive to mechanical stimuli. Finally, blocking of PIEZO1 channels after intraperitoneal injection of the toxin GsMTx4 reduced mechanically evoked scratching in naive mice.īased on these experiments, the authors conclude that subsets of peripheral slow conduction C-fibers expressing PIEZO1 promote itch and alloknesis upon mechanical stimulation. However, experimentally induced skin inflammation (mimicking AD) did not alter itch sensation in KO mice suggesting that PIEZO1 channels are not always required in chemical itch generation. In addition, in KO mice, the extent of itch induction by histamine and IL 31 was reduced. More, the authors showed that PIEZO1 can trigger acute itch as injection of Yoda1 (PIEZO1 agonist) leads to scratching in animals. This argues for the fact that PIEZO1 is present on histaminergic and non-histaminergic nerve fibers. 1 Murine PIEZO1 knockout (KO Piezo1fl/fl PirtCre+/− and Piezo1fl/fl SstCre+/−) experiments confirmed the role of PIEZO1 in alloknesis (scratching induced with stimulation with von Frey filaments) using the pruritogen histamine and IL 31 to create a CP state. PIEZO1 channels were shown to be functionally active in pruriceptive neurons, as PIEZO1 channels responded to stimulation with histamine and β-alanine (Mrgpr-agonist). Mrgpr receptors are highly associated with itch transmission. They identified PIEZO1 ion channels in murine and human Nppb-positive DRG neurons and murine MAS-related G-protein coupled receptor (Mrgpr) A3-positive nerves. Hill and colleagues 1 identified the exciting role of PIEZO1 in mechanical itch mediated by sensory neurons. However, this knowledge on the role of PIEZO2 does not explain the different types of mechanical itch as, for example, in mechanical-induced urticaria where histaminergic C-fibers are involved. This phenomenon is oftentimes observed in CP patients, as light touch (e.g., due to rubbing of clothes on skin) may induce an intolerable itch. This gate control homeostatic mechanism is lost under pathological CP conditions, for instance due to degeneration of MC, resulting in mechanical alloknesis. 5 Hence, in physiological states, tactile skin stimulation is perceived as light touch due to modulation of inhibitory spinal interneurons by input from MC/PIEZO2 expressing Aβ-LTMRs. 4 The MC/PIEZO2 channel unit modulates mechanical alloknesis under pathological conditions, as the loss of MC or the genetic ablation of PIEZO2 channels is associated with enhanced alloknesis in a murine dry skin model. The PIEZO protein family are mechano-sensitive calcium channels first described in 2010. More precisely, MC at the basal level of the epidermis are innervated by Aβ-LTMRs expressing PIEZO2 ion channels. 3 For example, Aβ nerve endings are associated with Merkel cells (MC) for mechanoreception in the skin and mediate discriminative touch under physiological conditions. In the skin, different aspects of tactile and mechanical sensations exist (light touch, emotional touch, perception of pressure, vibration, slip, texture) under physiological conditions, which are mediated by LTMR. This figure was edited by Elsevier Illustration Service CP chronic pruritus, DRG dorsal root ganglion, GRPR gastrin-release peptide receptor, H1R histamine 1 receptor, IL 31R interleukin 31 receptor, LTMR low-threshold mechanoreceptors, Mrgpr MAS-related G-protein coupled receptors, Nppb natriuretic polypeptide precursor B, NPY neuropeptide Y, NPY1R neuropeptide Y1 receptor, Tac2 tachykinin 2, Ucn3 urocortin 3. Conversely, in physiological conditions, gentle mechanical stimulation at a pleasurable intensity and pace (affective touch) are mediated by low-threshold mechano-sensitive C-fibers of hairy skin, projecting to lamina I-spinothalamic pathways. These fibers also react to histaminergic and non-histaminergic chemical pruritogens. Mechanical stimulation can, however, also induce itch and alloknesis via Nppb-positive DRG neurons expressing mechano-sensitive PIEZO1 channels. In CP states, this gate control is lost and light touch is perceived as itch (mechanical alloknesis). Inhibitory spinal interneurons are modulated by input from Merkel/PIEZO2 expressing Aβ LTMR. Spinal inhibitory NPY expressing interneurons suppress this pathway under physiological conditions, but may contribute to itch and alloknesis in a pathological state. Light tactile stimuli activate Aβ LTMR, which convey pruriceptive signals to spinal excitatory interneurons expressing Ucn3, Tac2, or NPY1R. Presumed mechanical itch transduction pathways.
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