Department of Pharmacology, Division of Molecular Pharmacology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
Nat Neurosci. 2018 Jun;21(6):820-833. doi: 10.1038/s41593-018-0144-y. Epub 2018 Apr 30.
Chronic morphine exposure upregulates adenylate cyclase signaling and reduces analgesic efficacy, a condition known as opioid tolerance. Nonopioid neurotransmitters can enhance morphine tolerance, but the mechanism for this is poorly understood. We show that morphine tolerance was delayed in mice lacking vasopressin 1b receptors (V1bRs) or after administration of V1bR antagonist into the rostral ventromedial medulla, where transcripts for V1bRs and μ-opioid receptors are co-localized. Vasopressin increased morphine-binding affinity in cells expressing both V1bR and μ-opioid receptors. Complex formation among V1bR, β-arrestin-2, and μ-opioid receptor resulted in vasopressin-mediated upregulation of ERK phosphorylation and adenylate cyclase sensitization. A leucine-rich segment in the V1bR C-terminus was necessary for the association with β-arrestin-2. Deletion of this leucine-rich segment increased morphine analgesia and reduced vasopressin-mediated adenylate cyclase sensitization. These findings indicate that inhibition of μ-opioid-receptor-associated V1bR provides an approach for enhancing morphine analgesia without increasing analgesic tolerance.
慢性吗啡暴露会上调腺苷酸环化酶信号转导并降低镇痛效果，这种情况称为阿片类药物耐受。非阿片类神经递质可以增强吗啡耐受，但这种机制尚不清楚。我们发现，缺乏血管加压素 1b 受体 (V1bR) 的小鼠或在延髓头端腹内侧区给予 V1bR 拮抗剂后，吗啡耐受延迟，而 V1bR 和 μ-阿片受体的转录本在该区域共定位。血管加压素增加了同时表达 V1bR 和 μ-阿片受体的细胞中吗啡的结合亲和力。V1bR、β-抑制蛋白-2 和 μ-阿片受体之间的复合物形成导致血管加压素介导的 ERK 磷酸化和腺苷酸环化酶敏化。V1bR C 端富含亮氨酸的片段对于与β-抑制蛋白-2 的关联是必需的。缺失该富含亮氨酸的片段可增加吗啡镇痛作用并减少血管加压素介导的腺苷酸环化酶敏化。这些发现表明，抑制 μ-阿片受体相关的 V1bR 提供了一种增强吗啡镇痛而不增加镇痛耐受的方法。
