Figure 1: Hair-pulling pain is a distinct PIEZO2-dependent pain submodality mediated by rapidly conducting fibers.

A–B. Individuals with PIEZO2 deficiency syndrome (PIEZO2^DS) exhibited a profound deficit in hair-pull pain perception (control participants: n=7, PIEZO2^DS individuals: n=6). A. At comparable forces, most hair-pull trials were reported as painful by control participants and nonpainful by PIEZO2^DS individuals. Dots represent individual trials (control participants: n=28 trials, PIEZO2^DS individuals: n=21 trials). B. The histograms represent the percentage of trials reported as painful (control participants: 92.8% vs. PIEZO2^DS individuals: 28.57%, p<0.0001; Fisher’s exact test). C. Hair-pulling evoked a readily discriminable percept. Control participants consistently distinguished between hair-pull pain and pinprick pain at equivalent pain intensity ratings (correct responses: hair pull 93.2 ± 6.0%, pinprick 86.2 ± 7.1%; n=15 trials per stimulus per participant; n=5 participants). Data are presented as individual- and pooled-mean (± SEM) responses in percentages. D–E. Hairpull pain elicited a nociceptive reflex. D. An example EMG recording of a nociceptive reflex response evoked by multi-hair pulling from a posterior arm muscle. E. Latency distribution of reflex responses recorded in anterior and posterior muscle compartments of the upper arm and corresponding pain ratings. Since no differences were found in reflex latencies and pain ratings (p>0.05; t-test) between the two compartments, the data were pooled. All reflex responses (n=23) were evoked at stimulus intensities rated as painful. Data are shown as individual and mean (±SEM) responses from 3 control participants (color-coded). F. Hair pulling evoked a distinct urge-to-move psychophysical response. Control participants chose to preferentially move towards the pain source in response to multi-hair pulling contrary to heating where they chose to move away (n=11 participants, p<0.001; Mann Whitney test, with hair pull urge vs. baseline: p=0.0585 and heat urge vs. baseline: p<0.001; Paired t-test). Data are presented as mean ± SEM. G–H. Hair-pull pain was scalable and mediated by Aβ fibers. G. Pain intensity ratings in response to single-hair pulling forces were assessed in control participants (n=20) at ‘Baseline’ and during preferential Aβ-fiber conduction ‘Block’, as well as in individuals with selective Aβ deafferentation (n=2). Pain intensity ratings were significantly affected by hair-pulling forces (F_(7,438) = 13.50, p<0.0001) and whether large myelinated fibers were conducting or not (F_(2,438) = 266.5, p<0.0001). During the conduction block, the hair-pull pain ratings decreased significantly across a range of pull forces (Baseline vs. Block: [50–800 mN]: p<0.0001). In addition, the Aβ-deafferented individuals were unable to perceive hair-pull pain. Statistical differences were assessed using a two-way ANOVA followed by Tukey’s multiple comparisons test. Data are presented as mean ± SEM. H. Quality of hair-pull pain assessed using the short-form McGill questionnaire in Baseline and Block conditions. The data show the number of occurrences (events) for each pain descriptor.