Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

Abstract

Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across <i>Mrgprs</i>, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to test the effect on pain in vivo. Here, we generated a transgenic mouse line in which we replaced mouse <i>Mrgprs</i> with human <i>MrgprX1</i> This humanized mouse allowed us to characterize an agonist [bovine adrenal medulla 8-22 (BAM8-22)] and a positive allosteric modulator (PAM), ML382, of MRGPRX1. Cellular studies suggested that ML382 enhances the ability of BAM8-22 to inhibit high-voltage-activated Ca²⁺ channels and attenuate spinal nociceptive transmission. Importantly, both BAM8-22 and ML382 effectively attenuated evoked, persistent, and spontaneous pain without causing obvious side effects. Notably, ML382 by itself attenuated both evoked pain hypersensitivity and spontaneous pain in <i>MrgprX1</i> mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized <i>MrgprX1</i> mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.