PIEZO2‐dependent rapid pain system in humans and mice

Abstract

SummaryThe PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception – a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare Aβ deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aβ input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

Experimental nerve block study on painful withdrawal reflex responses in humans

“…NWR relies on temporal summation driven by high-frequency repeated stimuli. In this context, the high impulse rates (up to 300 Hz) produced by Aβ nociceptors [23, 48] in response to noxious stimuli suggests that this class of afferent fiber is ideally suited for detection (and rapid relay) of information about noxious stimuli and to contribute to the generation of NWR. Indeed, the function of pain as a warning system necessitates the rapid transmission of information from the periphery to execute appropriate motor responses and meet behavioral requirements.…”