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 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.

• Authors: Zhe Li, Pang-Yen Tseng, Vinod Tiwari, Qian Xu, Shao-Qiu He, Yan Wang, Qin Zheng, Liang Han, Zhiping Wu, Anna L Blobaum, Yiyuan Cui, Vineeta Tiwari, Shuohao Sun, Yingying Cheng, Julie H Y Huang-Lionnet, Yixun Geng, Bo Xiao, Junmin Peng, Corey Hopkins, Srinivasa N Raja, Yun Guan, Xinzhong Dong
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 10 Pg. E1996-E2005 (03 07 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28223516 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Benzamides
• Calcium Channel Blockers
• Calcium Channels
• ML382 compound
• Peptide Fragments
• Receptors, G-Protein-Coupled
• Sulfonamides
• bovine adrenal medulla 8-22
• mas-related gene-X1 receptor, human

Topics

• Allosteric Regulation
• Analgesics (pharmacology)
• Animals
• Benzamides (pharmacology)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels (genetics, metabolism)
• Cattle
• Chronic Pain
• Disease Models, Animal
• Gene Expression
• Humans
• Male
• Mice
• Mice, Transgenic
• Nociception (drug effects)
• Peptide Fragments (pharmacology)
• Peripheral Nerve Injuries (drug therapy, pathology, physiopathology)
• Receptors, G-Protein-Coupled (agonists, genetics, metabolism)
• Sciatic Nerve (drug effects, injuries, physiopathology)
• Sulfonamides (pharmacology)
• Transgenes