Facilitation of MrgprD by TRP-A1 promotes neuropathic pain

Neuropathic pain remains a therapeutic challenge because of its complicated mechanisms. Mas-related GPCR D (MrgprD) is specifically expressed in small-diameter, nociceptive neurons of dorsal root ganglia (DRGs) and is implicated in pain modulation. However, the underlying mechanism of MrgprD involved in neuropathic pain remains elusive. In this study, we used behavioral experiments and physiologic examination methods to investigate the role of MrgprD in chronic constriction injury (CCI)–induced neuropathic pain. We found that MrgprD is necessary for the initiation of mechanical hypersensitivity and cold allodynia, but not for heat allodynia. Moreover, we demonstrated that transient receptor potential cation channel (TRP)-A1 was the ion channel downstream of MrgprD, and the β-alanine–induced calcium signal was attributed mostly to TRP-A1 function. We further showed that PKA serves as a downstream mediator of β-alanine–activated MrgprD signaling to activate TRP-A1 in DRG neurons and in human embryonic kidne...