Allosteric Modulator of Mas-Related G-Protein Coupled Receptor X1 (MrgprX1) Inhibits Persistent Pain
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Date
2016-01-28
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Johns Hopkins University
Abstract
Mas-related G-protein-coupled receptor subtype C and subtype X1 (mouse MrgprC11, rat MrgprC and human MrgprX1) are a novel group of receptors as promising targets of pain inhibitors, mainly because of their restricted expression in small diameter nociceptors within the peripheral nervous system. Drug screens have been conducted targeting at human MrgprX1. However, constrained by the species difference across Mrgprs, many drug candidates could activate MrgprX1 but not the rodent ones, leaving no animal model responsive to test the anti-chronic pain effect in vivo. Our laboratory recently generated a transgenic mouse line in which we replaced a cluster of twelve mouse Mrgprs (including MrgprC11) with human MrgprX1. This valuable humanized mouse line allowed us to characterize a potent positive allosteric modulator of MrgprX1, ML382. Cellular studies in humanized MrgprX1 mice suggest that ML382 enhances the ability of bovine adrenal medulla peptide (BAM22, or BAM8–22) as the orthosteric agonist to inhibit N-type voltage-activated calcium current through pertussis toxin sensitive Gi/o pathway. We then used several behavior tests to evaluate the analgesic effect of ML382 in inflammatory pain and neuropathic pain animal models. We also observed that MrgprX1 expressing animals developed strong conditioned place preference to ML382 paired chamber comparing to saline paired chamber. Importantly, ML382 effectively attenuates evoked persistent and spontaneous pain without causing peripheral or central side effects such as itch, motor dysfunction, or being rewarding for the uninjured naïve animals. Our findings suggest that humanized MrgprX1 mice provide an essential preclinical model and that allosterically activating MrgprX1 by ML382 is a novel and effective way of inhibiting persistent pain.
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Allosteric Modulator, Mas-Related G-Protein Coupled Receptor X1, Persistent Pain