Chronic pain is a major health and economic problem worldwide with an estimated prevalence reaching epidemic levels of >25% of the population. For example in the US, chronic pain affects over 116 million adults and costs up to $635 billion annually in treatment and lost productivity. Most drugs on the market for chronic pain have undesired side effects because their targets exist both inside and outside the pain pathways. MrgprX1, a human GPCR, is a promising target of novel pain inhibitors, mainly because of its restricted expression in pain-sensing neurons. Many pharmaceutical companies have conducted drug screens to target human MrgprX1. However, constrained by species differences across Mrgprs, many drug candidates activate MrgprX1 but not the rodent orthologues, leaving no animal model responsive to test the effect on pain in vivo. To overcome the species specificity problem, Xinzhong Dong's lab generated a transgenic mouse line in which they replaced mouse Mrgprs with human MrgprX1. This valuable humanized mouse allowed them to characterize a potent positive allosteric modulator of MrgprX1, ML382. Cellular studies in humanized MrgprX1 mice suggest that ML382 enhances the ability of MrgprX1 to inhibit N-type Ca2+ channels via the Gi pathway in nociceptive neurons and block presynaptic terminal transmission in spinal cord. Importantly, ML382 effectively attenuates evoked persistent and spontaneous pain without causing peripheral or central side effects such as itch, motor dysfunction, or reward in the naïve condition. The group's findings suggest that humanized MrgprX1 mice provide an essential preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.
Full Article in PNAS: http://www.pnas.org/content/early/2017/02/17/1615255114.full
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, and Xinzhong Dong
Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain
PNAS 2017 ; published ahead of print February 21, 2017, doi:10.1073/pnas.1615255114