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

Abstract

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. 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. 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.