Tissue injury and inflammation markedly alter touch perception, making normally innocuous sensations become intensely painful. Although this sensory distortion, known as tactile allodynia, is one of the most common types of pain, the mechanism by which gentle mechanical stimulation becomes unpleasant remains enigmatic. The stretch-gated ion channel PIEZO2 has been shown to mediate light touch, vibration detection, and proprioception. However, the role of this ion channel in nociception and pain has not been resolved. Here, we examined the importance of Piezo2 in the cellular representation of mechanosensation using in vivo imaging in mice. Piezo2-knockout neurons were completely insensitive to gentle dynamic touch but still responded robustly to noxious pinch. During inflammation and after injury, Piezo2 remained essential for detection of gentle mechanical stimuli. We hypothesized that loss of PIEZO2 might eliminate tactile allodynia in humans. Our results show that individuals with loss-of-function mutations in PIEZO2 completely failed to develop sensitization and painful reactions to touch after skin inflammation. These findings provide insight into the basis for tactile allodynia, identify the PIEZO2 mechanoreceptor as an essential mediator of touch under inflammatory conditions, and suggest that this ion channel might be targeted for treating tactile allodynia.

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Henry Miller stated that “to relieve a full bladder is one of the great human joys”. Urination is critically important in health, and ailments of the lower urinary tract (LUT) cause extensive pathological burden. Nevertheless, we take urination for granted, and in-depth mechanistic insight is lacking. We have witnessed advances in understanding the central circuitry in the brain that facilitates urination 1 – 3 . Beyond central control, micturition reflexes that govern urination are all initiated by peripheral mechanical stimuli such as bladder stretch and urethral flow 4 . Surprisingly, the mechanotransduction molecules and the cell types that function as the primary stretch and pressure detectors in the urinary tract are mostly unknown. We find that the mechanosensitive ion channel PIEZO2 is expressed in lower urinary tract tissues, where it is required for low-threshold bladder stretch sensing and urethral micturition reflexes. We show that PIEZO2 acts as a sensor in both the bladder urothelium and innervating sensory neurons. Importantly, both humans and mice lacking functional PIEZO2 have impaired bladder control, and humans report deficient bladder-filling sensation. This study pinpoints PIEZO2 as a key mechanosensor in urinary function. These findings enable future work that will unlock how urothelial cells and sensory neurons interact to control urination.