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Transl. Med."],"published-print":{"date-parts":[[2025,12,17]]},"abstract":"<jats:p>\n                    The human\n                    <jats:italic toggle=\"yes\">Mas<\/jats:italic>\n                    -related G protein\u2013coupled receptor X1 (MrgprX1) represents a promising nonopioid analgesic target because of its selective expression in primary nociceptive sensory neurons. Positive allosteric modulators (PAMs) promote receptor signaling, depending on the availability of endogenous ligands, offering physiological selectivity over orthosteric agonists. We developed an orally bioavailable MrgprX1 PAM, 6-tert-butyl-5-(4-chlorophenyl)-4-(2-fluoro-6-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine (BCFTP). BCFTP selectively potentiated the functional response of MrgprX1 in HEK293 cells, was metabolically stable, and demonstrated a favorable in vitro safety profile. BCFTP was orally bioavailable and distributed into the spinal cords of wild-type mice. BAM22, an endogenous ligand for MrgprX1, was up-regulated in the spinal cord after nerve injury in both wild-type and humanized MrgprX1 mice and was expressed in peptidergic and nonpeptidergic dorsal root ganglion neurons. Oral administration of BCFTP dose-dependently inhibited heat hyperalgesia and spontaneous pain-like behavior but not mechanical hypersensitivity after sciatic chronic constrictive injury (CCI) in MrgprX1 mice. BCFTP did not have analgesic effects in Mrgpr cluster knockout (Mrgpr\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) mice, indicating that the analgesic effects in MrgprX1 mice were MrgprX1 dependent. BCFTP enhanced BAM8-22\u2013induced, MrgprX1-mediated reduction of C-fiber eEPSC amplitudes in spinal lamina II neurons, indicating inhibition of spinal nociceptive synaptic transmission. BCFTP did not induce tolerance or side effects, such as itch, sedation, and motor incoordination, and had no rewarding properties. The mRNAs encoding MrgprX1 and \u03bc-opioid receptors were colocalized in human DRG neurons, and BCFTP synergistically enhanced morphine analgesia in CCI MrgprX1 mice. Our research suggests an approach for developing safer, orally bioavailable MrgprX1 PAM as a nonopioid therapy for neuropathic pain.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adw9446","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T19:00:39Z","timestamp":1765998039000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["An orally bioavailable MrgprX1-positive allosteric modulator alleviates certain neuropathic pain\u2013related behaviors in humanized mice"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3327-4166","authenticated-orcid":true,"given":"Ankit","family":"Uniyal","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8475-2591","authenticated-orcid":true,"given":"Niyada","family":"Hin","sequence":"additional","affiliation":[{"name":"Johns Hopkins Drug Discovery and Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7306-2243","authenticated-orcid":true,"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6227-7644","authenticated-orcid":true,"given":"Qian","family":"Xu","sequence":"additional","affiliation":[{"name":"Solomon H. 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