{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T15:43:19Z","timestamp":1776958999292,"version":"3.51.4"},"reference-count":82,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund","award":["FK_138389"],"award-info":[{"award-number":["FK_138389"]}]},{"name":"Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund","award":["TKP 2021 EGA-25"],"award-info":[{"award-number":["TKP 2021 EGA-25"]}]},{"name":"Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund","award":["EFOP-3.6.3-VEKOP-16-2017-00009"],"award-info":[{"award-number":["EFOP-3.6.3-VEKOP-16-2017-00009"]}]},{"name":"Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["FK_138389"],"award-info":[{"award-number":["FK_138389"]}]},{"name":"Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["TKP 2021 EGA-25"],"award-info":[{"award-number":["TKP 2021 EGA-25"]}]},{"name":"Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["EFOP-3.6.3-VEKOP-16-2017-00009"],"award-info":[{"award-number":["EFOP-3.6.3-VEKOP-16-2017-00009"]}]},{"name":"Semmelweis 250+ Kiv\u00e1l\u00f3s\u00e1gi PhD \u00d6szt\u00f6nd\u00edj","award":["FK_138389"],"award-info":[{"award-number":["FK_138389"]}]},{"name":"Semmelweis 250+ Kiv\u00e1l\u00f3s\u00e1gi PhD \u00d6szt\u00f6nd\u00edj","award":["TKP 2021 EGA-25"],"award-info":[{"award-number":["TKP 2021 EGA-25"]}]},{"name":"Semmelweis 250+ Kiv\u00e1l\u00f3s\u00e1gi PhD \u00d6szt\u00f6nd\u00edj","award":["EFOP-3.6.3-VEKOP-16-2017-00009"],"award-info":[{"award-number":["EFOP-3.6.3-VEKOP-16-2017-00009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Opioid analgesic tolerance (OAT), among other central side effects, limits opioids\u2019 indispensable clinical use for managing chronic pain. Therefore, there is an existing unmet medical need to prevent OAT. Extrasynaptic N-methyl D-aspartate receptors (NMDARs) containing GluN2B subunit blockers delay OAT, indicating the involvement of glutamate in OAT. Glycine acts as a co-agonist on NMDARs, and glycine transporters (GlyTs), particularly GlyT-1 inhibitors, could affect the NMDAR pathways related to OAT. Chronic subcutaneous treatments with morphine and NFPS, a GlyT-1 inhibitor, reduced morphine antinociceptive tolerance (MAT) in the rat tail-flick assay, a thermal pain model. In spinal tissues of rats treated with a morphine\u2013NFPS combination, NFPS alone, or vehicle-comparable changes in \u00b5-opioid receptor activation, protein and mRNA expressions were seen. Yet, no changes were observed in GluN2B mRNA levels. An increase was observed in glycine and glutamate contents of cerebrospinal fluids from animals treated with a morphine\u2013NFPS combination and morphine, respectively. Finally, GlyT-1 inhibitors are likely to delay MAT by mechanisms relying on NMDARs functioning rather than an increase in opioid efficacy. This study, to the best of our knowledge, shows for the first time the impact of GlyT-1 inhibitors on MAT. Nevertheless, future studies are required to decipher the exact mechanisms.<\/jats:p>","DOI":"10.3390\/ijms252011136","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T03:49:34Z","timestamp":1729136974000},"page":"11136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Glycine Transporter 1 Inhibitors Minimize the Analgesic Tolerance to Morphine"],"prefix":"10.3390","volume":"25","author":[{"given":"Anna Rita","family":"Galambos","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1085 Budapest, Hungary"},{"name":"Center for Pharmacology and Drug Research & Development, Semmelweis University, \u00dcll\u0151i \u00fat 26., H-1085 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3440-6263","authenticated-orcid":false,"given":"Nariman","family":"Essmat","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1085 Budapest, Hungary"},{"name":"Center for Pharmacology and Drug Research & Development, Semmelweis University, \u00dcll\u0151i \u00fat 26., H-1085 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e9ter P.","family":"Lakatos","sequence":"additional","affiliation":[{"name":"Center for Pharmacology and Drug Research & Development, Semmelweis University, \u00dcll\u0151i \u00fat 26., H-1085 Budapest, Hungary"},{"name":"Department of Pharmacodynamics, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, 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