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

Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):E1996-E2005. doi: 10.1073/pnas.1615255114. Epub 2017 Feb 21.


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.

Keywords: DRG neurons; GPCR; MrgprX1; pain; positive allosteric modulator.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Analgesics / pharmacology*
  • Animals
  • Benzamides / pharmacology*
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels / genetics
  • Calcium Channels / 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
  • Peripheral Nerve Injuries / pathology
  • Peripheral Nerve Injuries / physiopathology
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / injuries
  • Sciatic Nerve / physiopathology
  • Sulfonamides / pharmacology*
  • Transgenes


  • 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