PIEZO2-dependent rapid pain system in humans and mice.

Bouchatta, O.; Brodzki, M.; Manouze, H.; Carballo, G. B.; Kindstrom, E.; de-Faria, F. M.; Yu, H.; Kao, A. R.; Thorell, O.; Liljencrantz, J.; Ng, K. K.; Frangos, E.; Ragnemalm, B.; Saade, D.; Bharucha-Goebel, D.; Szczot, I.; Moore, W.; Terejko, K.; Cole, J.; Bonnemann, C.; Luo, W.; Mahns, D. A.; Larsson, M.; Gerling, G. J.; Marshall, A. G.; Chesler, A. T.; Olausson, H.; Nagi, S. S.; Szczot, M.

doi:10.1101/2023.12.01.569650

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bioRxiv · 10.1101/2023.12.01.569650

PIEZO2-dependent rapid pain system in humans and mice.

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Abstract

The 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 A{beta} deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on A{beta} 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.

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Bouchatta, O., Brodzki, M., Manouze, H., Carballo, G. B., Kindstrom, E., de-Faria, F. M., Yu, H., Kao, A. R., Thorell, O., Liljencrantz, J., Ng, K. K., Frangos, E., Ragnemalm, B., Saade, D., Bharucha-Goebel, D., Szczot, I., Moore, W., Terejko, K., Cole, J., Bonnemann, C., Luo, W., Mahns, D. A., Larsson, M., Gerling, G. J., Marshall, A. G., Chesler, A. T., Olausson, H., Nagi, S. S., Szczot, M.. 2023-12-02. PIEZO2-dependent rapid pain system in humans and mice.. https://doi.org/10.1101/2023.12.01.569650

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