Piezo2 mediates mechanical sensitivity and injury-induced hypersensitivity in MrgprD-expressing nociceptors

Piezo2 is a mechanotransducer essential for detecting low-threshold tactile and proprioceptive stimuli. Emerging evidence suggests its involvement in pain sensing, particularly in mechanical allodynia. Transcriptomic data revealed high Piezo2 expression in MrgprD-expressing neurons, a population of nonpeptidergic nociceptors implicated in physiological and pathological mechanical pain. However, the specific function of Piezo2 in these pain-sensing neurons and its potential contribution to mechanical hyperalgesia induced by nerve injury remains unclear. We used in vitro calcium imaging to functionally characterize MrgprD + neurons in adult mouse dorsal root ganglia (DRG) and performed whole-cell mechano patch-clamp recordings to characterize their mechanosensitivity. Approximately half of MrgprD + neurons displayed mechanically activated currents. These currents were abolished in MrgprD + DRG neurons from conditional knockout mice lacking Piezo2 specifically in this population. Behavioral experiments using the sciatic nerve chronic constriction injury mouse model revealed reduced mechanical hypersensitivity to high-intensity stimuli in mice lacking Piezo2 specifically in MrgprD + neurons. In vivo calcium imaging of lumbar DRG showed increased activity of MrgprD + neurons in response to noxious mechanical stimulation of the hind paw under chronic constriction injury-induced neuropathic pain. Conditional deletion of Piezo2 abolished this sensitization and significantly decreased the proportion of MrgprD + neurons responsive to mechanical stimuli. Collectively, these findings highlight Piezo2 as a key mediator of noxious mechanical sensitivity in MrgprD + neurons under both physiological and neuropathic pain conditions.