Background and aims: The canonical view is that pain in humans is signaled exclusively by slowly conducting, thinly myelinated (‘fast’ pain) or unmyelinated (‘slow’ pain) afferents. While other mammals have rapidly conducting nociceptors, these have not been demonstrated in humans. Methods: We performed single-unit axonal recordings (microneurography) from mechanoreceptive cutaneous afferents in the peroneal and radial nerves of healthy participants, and psychophysical observations in patient groups with selective deafferentation or channelopathy. Results: We identified myelinated high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and had conduction velocities similar to thickly myelinated low-threshold mechanoreceptors. Intra-neural electrical stimulation of single A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed that pain judgments to graded mechanical stimuli were impaired only in the condition of absent thickly myelinated fibers. This function was preserved in patients with loss-of-function mutation in mechanotransduction channel PIEZO2. Conclusions: Mechanical pain in humans does not require the PIEZO2 channel, and can be signaled by thickly myelinated, rapidly conducting afferents. Their existence in humans questions the validity of dichotomous fast touch-slow pain systems in classical teaching. This calls for a reappraisal of neurological views that mechanical pain examination specifically assesses small-fiber function, and that painful neuropathies imply small-fiber involvement, opening up novel therapeutic targets in pain disorders.

04 - AN ULTRA-FAST SYSTEM FOR SIGNALING MECHANICAL PAIN IN HUMAN SKIN