PIEZO2-dependent rapid pain system in humans.

The diversity of mechanical pain sensations in humans cannot be explained based on our current understanding of pain-sensing neural classes in the skin. To begin to bridge this gap, we dissected the neural basis of a distinct form of pain sensation evoked by hair pulling in humans. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Single-unit axonal recordings revealed a specific class of cooling-responsive, rapidly conducting nociceptors are selectively tuned to painful hair-pull stimuli. We pharmacologically map these nociceptors to a specific transcriptomic class and demonstrate that myelinated nociceptors are anatomically associated with hair follicles. Using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Finally, studies in control participants show that noxious hair-pull stimuli trigger a distinct nocifensive response, including a rapid nociceptive reflex; further, observations in rare Aβ-deafferented individuals and nerve conduction block studies reveal that hair-pull pain perception is dependent on Aβ-fiber input. Together, we identify a previously unknown class of human nociceptors and characterize its functional and molecular features.