Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance

Taka Aki Koshimizu, Kenji Honda, Sachi Nagaoka-Uozumi, Atsuhiko Ichimura, Ikuo Kimura, Nakaya Michio, Nobuya Sakai, Katsushi Shibata, Kentarou Ushijima, Akio Fujimura, Akira Hirasawa, Hitoshi Kurose, Gozoh Tsujimoto, Akito Tanoue, Yukio Takano

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)820-833
Number of pages14
JournalNature Neuroscience
Volume21
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

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Vasopressin Receptors
Opioid Receptors
Morphine
Vasopressins
Adenylyl Cyclases
Leucine
Analgesia
Analgesics
Up-Regulation
Opioid Analgesics
Neurotransmitter Agents
beta-Arrestin 1
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance. / Koshimizu, Taka Aki; Honda, Kenji; Nagaoka-Uozumi, Sachi; Ichimura, Atsuhiko; Kimura, Ikuo; Michio, Nakaya; Sakai, Nobuya; Shibata, Katsushi; Ushijima, Kentarou; Fujimura, Akio; Hirasawa, Akira; Kurose, Hitoshi; Tsujimoto, Gozoh; Tanoue, Akito; Takano, Yukio.

In: Nature Neuroscience, Vol. 21, No. 6, 01.06.2018, p. 820-833.

Research output: Contribution to journalArticle

Koshimizu, TA, Honda, K, Nagaoka-Uozumi, S, Ichimura, A, Kimura, I, Michio, N, Sakai, N, Shibata, K, Ushijima, K, Fujimura, A, Hirasawa, A, Kurose, H, Tsujimoto, G, Tanoue, A & Takano, Y 2018, 'Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance', Nature Neuroscience, vol. 21, no. 6, pp. 820-833. https://doi.org/10.1038/s41593-018-0144-y
Koshimizu, Taka Aki ; Honda, Kenji ; Nagaoka-Uozumi, Sachi ; Ichimura, Atsuhiko ; Kimura, Ikuo ; Michio, Nakaya ; Sakai, Nobuya ; Shibata, Katsushi ; Ushijima, Kentarou ; Fujimura, Akio ; Hirasawa, Akira ; Kurose, Hitoshi ; Tsujimoto, Gozoh ; Tanoue, Akito ; Takano, Yukio. / Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance. In: Nature Neuroscience. 2018 ; Vol. 21, No. 6. pp. 820-833.
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