Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Abstract

Background Visceral hypersensitivity, an important cause of abdominal pain in disorders such as IBD and IBS, presents with a poorly understood pathophysiology and limited treatment options. Several members of the Mas‐related G protein‐coupled receptor family (Mrgprs) have become promising targets in pain research. The potential link between the murine Mrgpr C11 (Mrgprc11) and gut nociception is currently uninvestigated. Therefore, we explored the expression and functional role of Mrgprc11 in the gut nociceptive innervation. Methods Mrgprc11 expression was evaluated in DRG neurons innervating the mouse colon using in situ hybridization and immunohistochemistry. Visceromotor responses to colorectal distension (CRD) assessed the effect of the Mrgprc11 agonist, BAM(8‐22), on colonic pain sensitivity in healthy mice. Moreover, we determined pERK1/2‐immunoreactivity in the thoracolumbar spinal cord after noxious CRD. Finally, from a translational point of view, we looked for expression of the human counterpart of Mrgprc11, MRGPRX1, in human thoracolumbar DRGs. Key Results In situ hybridization and immunohistochemistry revealed Mrgprc11 expression in colonic DRG neurons. Intracolonic administration of BAM(8‐22) significantly increased colonic pain sensitivity in an Mrgprc11‐dependent manner, and led to a significantly increased degree of neuronal activation in the splanchnic spinal cord upon noxious stimulation. Furthermore, MRGPRX1 expression was also detected in human thoracolumbar DRG neurons. Conclusions & Inferences Our findings established a novel function for Mrgprc11 in the gut nociceptive innervation and propose the receptor as a new player in visceral hypersensitivity. Given the presence of MRGPRX1 in human DRG neurons, our study warrants future research on its therapeutic potential in abdominal pain disorders.

Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivity

“…In the case of BAM8-22, visceral hypersensitivity to CRD was observed at more noxious distension pressures. This is consistent with very recent findings showing that BAM8-22 evoked elevated pain responses to CRD in healthy mice (40). While intracolonic administration of the individual agonists for TGR5, MrgprA3, and MrgprC11 evoked hypersensitivity to CRD, they did not fundamentally affect spontaneous animal behavior.…”

“…The sensitizing effects of TGR5, MrgprA3, or MrgprC11 agonists on colonic afferents likely occurs via neuronal mechanisms. This is because MRGPRA3 and MRGPRC11 (40) are absent from colonic tissues but are expressed on mouse and human DRG neurons. While TGR5 is expressed on colonic afferents, it is also expressed on colonic epithelial cells and on enteric neurons (41, 42).…”

Identification of potential biomarkers for abdominal pain in IBS patients by bioinformatics approach

“…In the colon, afferent sensitization occurs via a variety of processes [18], including histamine-dependent mechanisms and histamine-independent mechanisms [19,20]; Evidence have been accumulated that activation of receptors associated with the above two itch pathways on colon-innervating afferents induces visceral hypersensitivity [19,21]. Gastrin-releasing peptide receptor expressing (GRPR)+ neurons have a central role in the spinal transmission of both histaminergic and Fig.…”

Identification of Potential Biomarkers for Abdominal Pain in IBS Patients by Bioinformatics Approach

“…In the colon, afferent sensitization occurs via a variety of processes [16], including histamine-dependent mechanisms and histamine-independent mechanisms [17,18]; Evidence have been accumulated that activation of receptors associated with the above two itch pathways on colon-innervating afferents induces visceral hypersensitivity [17,19]. Gastrin-releasing peptide receptor expressing(GRPR) + neurons have a central role in the spinal transmission of both histaminergic and non-histaminergic itch [20].In our study, GRPR was signi cantly upregulated in IBS-D patients and identi ed as a hub gene by MCODE.…”