Abstract：
: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.
journal_name
Nat Neuroscijournal_title
Nature neuroscienceauthors
Koshimizu TA,Honda K,Nagaoka-Uozumi S,Ichimura A,Kimura I,Nakaya M,Sakai N,Shibata K,Ushijima K,Fujimura A,Hirasawa A,Kurose H,Tsujimoto G,Tanoue A,Takano Ydoi
10.1038/s41593-018-0144-ysubject
Has Abstractpub_date
2018-06-01 00:00:00pages
820-833issue
6eissn
1097-6256issn
1546-1726pii
10.1038/s41593-018-0144-yjournal_volume
21pub_type
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