Facilitation of MrgprD by TRP-A1 promotes neuropathic pain

Changming Wang, Leying Gu, Yonglan Ruan, Xiao Geng, Miao Xu, Niuniu Yang, Lei Yu, Yucui Jiang, Chan Zhu, Yan Yang, Yuan Zhou, Xiaowei Guan, Wenqin Luo, Qin Liu, Xinzhong Dong, Guang Yu, Lei Lan, Zongxiang Tang

Research output: Contribution to journalArticle

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 b-alanine-induced calcium signal was attributed mostly to TRP-A1 function.We further showed that PKA serves as a downstream mediator of b-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 b-alanine-induced pain behavior was increased, whereas theitching behavior was unchangedin CCI models compared with sham-injured animals. Knockout of TRPA1 also attenuated the b-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.

Original languageEnglish (US)
Pages (from-to)1360-1373
Number of pages14
JournalFASEB Journal
Volume33
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • Dorsal root ganglia (DRG)
  • MrgprA1
  • Protein kinase A (PKA)

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    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. (2019). Facilitation of MrgprD by TRP-A1 promotes neuropathic pain. FASEB Journal, 33(1), 1360-1373. https://doi.org/10.1096/fj.201800615RR