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.

Sensitization of small‐diameter sensory neurons is controlled by TRPV1 and TRPA1 association

“…46 Recent single-cell RNA-sequencing data 27 and electrophysiology profiling of DRG sensory neurons 4 showed that there are two distinct MrgprD + subgroups (S4 and S5) representing C-mechano-heat and C-mechanosensitive nociceptors 46 . 47 This may explain that the disruption of TRPV1-TRPA1 complex with ID peptides did not reverse neuropathic pain induced by CCI ( Figure 7D-F). 1,16 These neurons are not transiently sensitized by inflammatory mediators; however, recent reports show TRPA1positive MrgprD + neurons promote neuropathic pain.…”

“…In chronic nerve injury pain conditions, TRPA1 could undergo upregulation that leads to long-term sensitization in MrgprD + neurons, which is independent of TRPV1. 47 This may explain that the disruption of TRPV1-TRPA1 complex with ID peptides did not reverse neuropathic pain induced by CCI ( Figure 7D-F). The third subgroup (S6) is the TRPV1 + /CGRPneurons.…”

“…The second subgroup is MrgprD + DRG neurons, which are itch-sensing neurons 45 and also encode C-mechano-heat nociceptors. 47 This implies that MrgprD + neurons could be more important for nerve damage compared to inflammatory pain. One of these groups (S4) express TRPA1, 4,46 but neither expresses TRPV1 or Tmem100.…”

“…16 Disruption of the V1-A1 complex with cell-permeable ID peptide, representing two distinct association domains on TRPV1, also results in attenuation of inflammatory, but nerve damage-induced hypersensitivity. 47 Ablation of the A1-V1 complex by ID peptides provides two distinct benefits over targeting Tmem100. It means ID peptide is lesser effective at the peripheral compared to spinal site.…”

Evoked and spontaneous pain assessment during tooth pulp injury

“…The authors suggest that the interaction between TRPA1 and Mrgprd may be broadly important for the development of mechanical allodynia 42 . Very recent evidence suggests that Mrgprd activation by its agonist beta-alanine results in phosphorylation of TRPA1 via Protein Kinase A 43 , but it is not clear if TRPA1 may also influence any aspect of Mrgprd expression or function. The overlap of TRPA1 and Mrgprd in the tooth pulp afferents has not been explored.…”