{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:25:48Z","timestamp":1791570348462,"version":"4.3.4"},"reference-count":84,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2022R1A6A1A03054419"],"award-info":[{"award-number":["2022R1A6A1A03054419"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Extensive research has focused on developing anti-nociceptive therapy by targeting specific molecular pathways. Among these, the serotonin 2A receptor (5-HT2AR) and metabotropic glutamate receptor 5 (mGluR5) are recognized as key mediators of neuropathic pain. However, the therapeutic potential of their simultaneous inhibition remains largely unexplored. In this study, we evaluated the efficacy of dual antagonism of 5-HT2AR and mGluR5 using spinal nerve ligation (SNL) and formalin-induced pain models in male Sprague\u2013Dawley rats. Co-administration of selective antagonists significantly enhanced anti-allodynic and anti-nociceptive effects, as evidenced by increased withdrawal thresholds and reduced pain-related behaviors compared to monotherapy. The analgesic efficacy of dual antagonism was comparable to that of gabapentin and morphine. Additionally, novel small molecules designed to concurrently inhibit 5-HT2AR and mGluR5 exerted dose-dependent anti-nociceptive effects by suppressing excitatory postsynaptic responses and inhibiting the phosphorylation of ERK and AKT signaling molecules. Importantly, unlike morphine, repeated administration of the dual antagonist maintained anti-allodynic efficacy with a low potential of abuse. These findings may indicate the promise of simultaneous 5-HT2AR and mGluR5 antagonism as a novel and potentially safer strategy for managing chronic neuropathic pain.<\/jats:p>","DOI":"10.3390\/biom15101456","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T10:12:29Z","timestamp":1760523149000},"page":"1456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Enhanced Anti-Nociception by Novel Dual Antagonists for 5-HT2AR and mGluR5 in Preclinical Models of Pain"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6167-3372","authenticated-orcid":false,"given":"Daekyu","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Research Institute and Drug Development, Vivozon, Inc., Yongin-si 16914, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0118-8681","authenticated-orcid":false,"given":"Hyun Jin","family":"Heo","sequence":"additional","affiliation":[{"name":"Department of Research Institute and Drug Development, Vivozon, Inc., Yongin-si 16914, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haeyoung","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Research Institute and Drug Development, Vivozon, Inc., Yongin-si 16914, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayzoon","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Research Institute and Drug Development, Vivozon, Inc., Yongin-si 16914, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geonho","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Research Institute and Drug Development, Vivozon, Inc., Yongin-si 16914, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ah Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Research Institute and Drug Development, Vivozon, Inc., Yongin-si 16914, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwang-Hyun","family":"Hur","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoonmi","family":"Nho","sequence":"additional","affiliation":[{"name":"Department of Research Institute and Drug Development, Vivozon, Inc., Yongin-si 16914, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0854-5008","authenticated-orcid":false,"given":"Choon-Gon","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4793-1923","authenticated-orcid":false,"given":"Hanmi","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Research Institute and Drug Development, Vivozon, Inc., Yongin-si 16914, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1385\/MN:30:2:117","article-title":"Serotonin in pain and analgesia: Actions in the periphery","volume":"30","author":"Sommer","year":"2004","journal-title":"Mol. 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