Investigating the effects of global gene knockout of MrgF on motor performance and pain sensitivity in mice.

Abstract

Mas-related G protein-coupled receptors (Mrgs) are a subset of GPCRs linked to pain modulation. MrgF was identified as an orphan Mrg whose function and ligand remain unclear. In this study, in addition to its expression in the dorsal root ganglia (DRG), the primary afferent center that transmits pain, we identified dense expression of MrgF, particularly concentrated in the Purkinje cell layer of the mouse cerebellum. Given the the important role of Purkinje neurons in both motor modulation and non-motor modulation, including pain processing, we established a MrgF knockout mouse (MrgF^-/-) model and performed a battery of behavioral tests to explore motor performance and assess pain-associated responses. MrgF^-/- mice exhibited no disturbances in coordination and motor balance during the rotarod, pole, balance beam, and treadmill tests, and normal cerebellar histology was retained. In hot plate assays, MrgF^-/- mice displayed reduced pain-related behavioral responses to thermal stimuli, although no significance differences were found in tail flick assays between MrgF^-/- and wild-type (wt) mice. Moreover, in formalin tests, MrgF^-/- mice also showed decreased chemical-induced nociception. This was accompanied by a downregulation in the expression levels of genes associated with nociceptive modulation, such as c-fos, Runx1, Nav1.7, Nav1.8, and Nav1.9, within the DRG of MrgF^-/- mice. Taken together, our findings suggest that MrgF may play a significant role in modulating pain sensitivity, thereby advancing the understanding of the functional characteristics of the Mrgs family.