Facilitation of MrgprD by TRP‐A1 promotes neuropathic pain

ABSTRACT 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 kidney 293 cells, to coexpress MrgprD and TRP‐A1 plasmids. Finally, we found that the β‐alanine–induced pain behavior was increased, whereas the itching behavior was unchanged in CCI models compared with sham‐injured animals. Knockout of TRPA1 also attenuated the β‐alanine–induced pain behavior in CCI models. In conclusion, MrgprD is essential in cold allodynia in CCI‐induced neuropathic pain through the PKA–TRP‐A1 pathway. TRP‐A1 facilitates MrgprD to development of neuropathic pain. Our findings reveal a novel mechanism of neuropathic pain formation and highlight MrgprD as a promising drug target for the treatment of neuropathic pain.—Wang, C., Gu, L., Ruan, Y., Geng, X., Xu, M., Yang, N., Yu, L., Jiang, Y., Zhu, C., Yang, Y., Zhou, Y., Guan, X., Luo, W., Liu, Q., Dong, X., Yu, G., Lan, L., Tang, Z. Facilitation of MrgprD by TRP‐A1 promotes neuropathic pain. FASEB J. 33, 1360–1373 (2019). www.fasebj.org