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Sci Adv. 2019 Jul 3;5(7):eaaw1297. doi: 10.1126/sciadv.aaw1297. eCollection 2019 Jul.

An ultrafast system for signaling mechanical pain in human skin.

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Center for Social and Affective Neuroscience, Linköping University, S-581 85 Linköping, Sweden.
Department of Clinical Neurophysiology, Linköping University Hospital, S-581 85 Linköping, Sweden.
School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia.
Faculty of Life Sciences, University of Manchester, M13 9PL Manchester, UK.
School of Natural Sciences and Psychology, Liverpool John Moores University, L3 3AF Liverpool, UK.
Department of Integrative Medical Biology, Umeå University, S-901 87 Umeå, Sweden.
National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Anesthesiology and Intensive Care, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden.
Department of Surgery, Unit of Orthopedics, Perioperative Sciences, Umeå University Hospital, 901 85 Umeå, Sweden.
School of Dentistry, Institute of Clinical Sciences, University of Liverpool, L3 5PS Liverpool, UK.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Dental Medicine, Karolinska Institute, S-141 04 Huddinge, Sweden.
Centre of Postgraduate Medical Research and Education, Bournemouth University, Poole BH12 5BB, UK.
Institute of Psychology, Health and Society, University of Liverpool, L3 5DA Liverpool, UK.


The canonical view is that touch is signaled by fast-conducting, thickly myelinated afferents, whereas pain is signaled by slow-conducting, thinly myelinated ("fast" pain) or unmyelinated ("slow" pain) afferents. While other mammals have thickly myelinated afferents signaling pain (ultrafast nociceptors), these have not been demonstrated in humans. Here, we performed single-unit axonal recordings (microneurography) from cutaneous mechanoreceptive afferents in healthy participants. We identified A-fiber high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and displayed conduction velocities similar to A-fiber low-threshold mechanoreceptors. Intraneural electrical stimulation of single ultrafast A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed impaired pain judgments to graded mechanical stimuli only when thickly myelinated fibers were absent. This function was preserved in patients with a loss-of-function mutation in mechanotransduction channel PIEZO2. These findings demonstrate that human mechanical pain does not require PIEZO2 and can be signaled by fast-conducting, thickly myelinated afferents.

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