title: 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 acrossMrgprs, 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 mouseMrgprswith humanMrgprX1This 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 inMrgprX1mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanizedMrgprX1mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Pang-Yen
authors.initials: PY
authors.lastname: Tseng
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Vinod
authors.initials: V
authors.lastname: Tiwari
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Shao-Qiu
authors.initials: SQ
authors.lastname: He
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.|Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.affiliation: The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Vineeta
authors.initials: V
authors.lastname: Tiwari
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Shuohao
authors.initials: S
authors.lastname: Sun
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Julie H Y
authors.initials: JH
authors.lastname: Huang-Lionnet
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Yixun
authors.initials: Y
authors.lastname: Geng
authors.affiliation: The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.|Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.|St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Corey
authors.initials: C
authors.lastname: Hopkins
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Srinivasa N
authors.initials: SN
authors.lastname: Raja
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; xdong2@jhmi.edu yguan1@jhmi.edu.
authors.forename: Yun
authors.initials: Y
authors.lastname: Guan
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; xdong2@jhmi.edu yguan1@jhmi.edu.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
mesh_terms: D000494:Allosteric Regulation; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D059350:Chronic Pain; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D059225:Nociception / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D059348:Peripheral Nerve Injuries / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D013449:Sulfonamides / Q000494:pharmacology*; D019076:Transgenes
chemical_list: D000700:Analgesics; D001549:Benzamides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; C000600806:ML382 compound; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; C571042:bovine adrenal medulla 8-22; C510803:mas-related gene-X1 receptor, human
keywords: DRG neurons; GPCR; MrgprX1; pain; positive allosteric modulator