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.

Highlights d A descending brainstem circuit controls behavioral responses to noxious stimuli d Parabrachial to reticular formation connections coordinate nocifensive escape d The parabrachial and reticular formation neurons in this circuit express Tac1 d Activation of the circuit amplifies escape behavior

SUMMARY The somatosensory system provides animals with the ability to detect, distinguish and respond to diverse thermal, mechanical and irritating stimuli. While there has been progress in defining classes of neurons underlying temperature sensation and gentle touch, less is known about the neurons specific for mechanical pain. Here, we use in vivo functional imaging to identify a class of cutaneous sensory neurons that are selectively activated by high threshold mechanical stimulation (HTMRs). We show that their optogenetic excitation evokes rapid protective and avoidance behaviors. Unlike other nociceptors, these HTMRs are fast conducting Ad-fibers with highly specialized circumferential endings wrapping the base of individual hair follicles. Notably, we find that Ad-HTMRs innervate unique but overlapping fields and can be activated by stimuli as precise as the pulling of a single hair. Together the distinctive features of this class of Ad-HTMRs appear optimized for accurate and rapid localization of mechanical pain.