Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain.
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 Mrgprs, 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 Mrgprs with human MrgprX1 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 MrgprX1 mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized MrgprX1 mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.
['Li|Zhe|Z|', 'Tseng|Pang-Yen|PY|', 'Tiwari|Vinod|V|', 'Xu|Qian|Q|', 'He|Shao-Qiu|SQ|', 'Wang|Yan|Y|', 'Zheng|Qin|Q|', 'Han|Liang|L|', 'Wu|Zhiping|Z|', 'Blobaum|Anna L|AL|', 'Cui|Yiyuan|Y|', 'Tiwari|Vineeta|V|', 'Sun|Shuohao|S|', 'Cheng|Yingying|Y|', 'Huang-Lionnet|Julie H Y|JH|', 'Geng|Yixun|Y|', 'Xiao|Bo|B|', 'Peng|Junmin|J|', 'Hopkins|Corey|C|', 'Raja|Srinivasa N|SN|', 'Guan|Yun|Y|', 'Dong|Xinzhong|X|']
D000494:Allosteric Regulation D000700:Analgesics D000818:Animals D001549:Benzamides D002121:Calcium Channel Blockers D015220:Calcium Channels D002417:Cattle D059350:Chronic Pain D004195:Disease Models, Animal D015870:Gene Expression D006801:Humans D008297:Male D051379:Mice D008822:Mice, Transgenic D059225:Nociception D010446:Peptide Fragments D059348:Peripheral Nerve Injuries D043562:Receptors, G-Protein-Coupled D012584:Sciatic Nerve D013449:Sulfonamides D019076:Transgenes
pain MrgprX1 positive allosteric modulator DRG neurons GPCR