Innocuous pressure sensation requires A-type afferents but not functional ΡΙΕΖΟ2 channels in humans

Abstract

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aβ fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aβ afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection.

Patch-seq of mouse DRG neurons reveals candidate genes for specific mechanosensory functions

“…Importantly, IA and slow-type MS currents are largely unaffected in Piezo2 KO DRG neurons (Ranade et al, 2014b), demonstrating that as-yet-unknown MS channels must account for the other MS currents. It is worthwhile to identify these channels since many sensations related to innocuous and noxious mechanical stimuli are independent from PIEZO2 in humans (Case et al, 2021;Chesler et al, 2016;Szczot et al, 2018). Recently, two other genes, namely, Tmem120a (Tacan) and Tmem150c (Tentonin 3), have been proposed to encode ion channels sustaining slow MS currents in DRG neurons (Beaulieu-Laroche et al, 2020;Hong et al, 2016), but some of these findings are controversial (Anderson et al, 2018;Dubin et al, 2017).…”

Patch-seq of mouse DRG neurons reveals candidate genes for specific mechanosensory functions

“…Importantly, IA and slow-type MS currents are largely unaffected in Piezo2 KO DRG neurons (Ranade et al, 2014b), demonstrating that as-yet-unknown MS channels must account for the other MS currents. It is worthwhile to identify these channels since many sensations related to innocuous and noxious mechanical stimuli are independent from PIEZO2 in humans (Case et al, 2021; Chesler et al, 2016; Szczot et al, 2018). Recently, two other genes, namely Tmem120a (Tacan) and Tmem150c (Tentonin 3), have been proposed to encode ion channels sustaining slow MS currents in DRG neurons (Beaulieu-Laroche et al, 2020; Hong et al, 2016), but some of these findings are controversial (Anderson et al, 2018; Dubin et al, 2017).…”

Nobel somatosensations and pain

“…This phenomenon is attributed to ‘central sensitization’: Enhanced transmission of non-nociceptive input to spinal dorsal horn neurons in the nociceptive pathway; transient noxious stimulation can temporarily induce this condition and heating capsaicin-treated skin is a human model. Applying this model to the patients with a loss-of-function mutation in the gene for PIEZO2 failed to cause tactile allodynia, consistent with their inability to detect light touch and vibration but in contrast to their largely retained perception of innocuous and noxious pressure [ 29 , 163 ]. These results are in agreement with findings from conditional PIEZO2 knockout mice that showed major deficits in responsiveness to various weak mechanical stimuli but only minor reduction of responses to pin prick and pinch.…”