Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance
Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance
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DOI：
10.1038/s41593-018-0144-y
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发表时间：
2018-06-01
影响因子：
25
通讯作者：
Takano, Yukio
中科院分区：
文献类型：
--
作者：
Koshimizu, Taka-aki;Honda, Kenji;Takano, Yukio
慢性吗啡暴露上调腺苷酸环化酶信号传导并降低镇痛功效，这是一种称为阿片耐受的状况。非阿片类神经递质可以增强吗啡耐受性，但其机制尚不清楚。我们发现，吗啡耐受性延迟在缺乏加压素1b受体（V1 bRs）的小鼠或给药后的V1 bR拮抗剂到延髓头端腹内侧，V1 bRs和μ阿片受体的转录本共定位。加压素增加吗啡结合亲和力的细胞表达V1 bR和μ阿片受体。V1 bR、β-抑制蛋白-2和μ-阿片受体之间的复合物形成导致加压素介导的ERK磷酸化上调和腺苷酸环化酶致敏。在V1 bR的C-末端的亮氨酸丰富的部分是必要的协会与β-逮捕-2。这个富含亮氨酸的片段的缺失增加了吗啡镇痛和减少了加压素介导的腺苷酸环化酶敏感性。这些发现表明，μ阿片受体相关的V1 bR抑制提供了一种方法，用于增强吗啡镇痛，而不增加镇痛耐受性。
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 mu-opioid receptors are co-localized. Vasopressin increased morphine-binding affinity in cells expressing both V1bR and mu-opioid receptors. Complex formation among V1bR, beta-arrestin-2, and mu-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 beta-arrest-in-2. Deletion of this leucine-rich segment increased morphine analgesia and reduced vasopressin-mediated adenylate cyclase sensitization. These findings indicate that inhibition of mu-opioid-receptor-associated V1bR provides an approach for enhancing morphine analgesia without increasing analgesic tolerance.