Oxytocin Is a Positive Allosteric Modulator of κ-Opioid Receptors but Not δ-Opioid Receptors in the G Protein Signaling Pathway
Kanako Miyano,
Yuki Yoshida,
Shigeto Hirayama,
Hideki Takahashi,
Haruka Ono,
Yoshiyuki Meguro,
Sei Manabe,
Akane Komatsu,
Miki Nonaka,
Takaaki Mizuguchi,
Hideaki Fujii,
Yoshikazu Higami,
Minoru Narita,
Yasuhito Uezono
Affiliations
Kanako Miyano
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
Yuki Yoshida
Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
Shigeto Hirayama
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan
Hideki Takahashi
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan
Haruka Ono
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan
Yoshiyuki Meguro
Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan
Sei Manabe
Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
Akane Komatsu
Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan
Miki Nonaka
Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan
Takaaki Mizuguchi
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan
Hideaki Fujii
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan
Yoshikazu Higami
Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
Minoru Narita
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
Yasuhito Uezono
Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan
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 μ-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 δ-OR (DOR) or κ-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 β-arrestin signaling. Thus, OT has potential as a specific signaling-biased PAM of KOR.
