{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:10:01Z","timestamp":1790626201239,"version":"4.1.0"},"reference-count":64,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T00:00:00Z","timestamp":1633305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science","award":["18K07404"],"award-info":[{"award-number":["18K07404"]}]},{"name":"Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science","award":["20K07750"],"award-info":[{"award-number":["20K07750"]}]},{"name":"Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science","award":["21K06584"],"award-info":[{"award-number":["21K06584"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Oxytocin (OT) influences various physiological functions such as uterine contractions, maternal\/social behavior, and analgesia. Opioid signaling pathways are involved in one of the analgesic mechanisms of OT. We previously showed that OT acts as a positive allosteric modulator (PAM) and enhances \u03bc-opioid receptor (MOR) activity. In this study, which focused on other opioid receptor (OR) subtypes, we investigated whether OT influences opioid signaling pathways as a PAM for \u03b4-OR (DOR) or \u03ba-OR (KOR) using human embryonic kidney-293 cells expressing human DOR or KOR, respectively. The CellKeyTM results showed that OT enhanced impedance induced by endogenous\/exogenous KOR agonists on KOR-expressing cells. OT did not affect DOR activity induced by endogenous\/exogenous DOR agonists. OT potentiated the KOR agonist-induced Gi\/o protein-mediated decrease in intracellular cAMP, but did not affect the increase in KOR internalization caused by the KOR agonists dynorphin A and (-)-U-50488 hydrochloride (U50488). OT did not bind to KOR orthosteric binding sites and did not affect the binding affinities of dynorphin A and U50488 for KOR. These results suggest that OT is a PAM of KOR and MOR and enhances G protein signaling without affecting \u03b2-arrestin signaling. Thus, OT has potential as a specific signaling-biased PAM of KOR.<\/jats:p>","DOI":"10.3390\/cells10102651","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T09:24:15Z","timestamp":1633339455000},"page":"2651","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Oxytocin Is a Positive Allosteric Modulator of \u03ba-Opioid Receptors but Not \u03b4-Opioid Receptors in the G Protein Signaling Pathway"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1673-6074","authenticated-orcid":false,"given":"Kanako","family":"Miyano","sequence":"first","affiliation":[{"name":"Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8293-2236","authenticated-orcid":false,"given":"Shigeto","family":"Hirayama","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Meguro","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sei","family":"Manabe","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akane","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6481-0294","authenticated-orcid":false,"given":"Miki","family":"Nonaka","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Mizuguchi","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikazu","family":"Higami","sequence":"additional","affiliation":[{"name":"Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Narita","sequence":"additional","affiliation":[{"name":"Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"name":"Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhito","family":"Uezono","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,4]]},"reference":[{"key":"ref_1","first-page":"8","article-title":"Molecular cloning and functional expression of a mu-opioid receptor from rat brain","volume":"44","author":"Chen","year":"1993","journal-title":"Mol. 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