| First Author | Koshimizu TA | Year | 2018 |
| Journal | Nat Neurosci | Volume | 21 |
| Issue | 6 | Pages | 820-833 |
| PubMed ID | 29713080 | Mgi Jnum | J:264677 |
| Mgi Id | MGI:6196662 | Doi | 10.1038/s41593-018-0144-y |
| Citation | Koshimizu TA, et al. (2018) Complex formation between the vasopressin 1b receptor, beta-arrestin-2, and the mu-opioid receptor underlies morphine tolerance. Nat Neurosci 21(6):820-833 |
| abstractText | 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-arrestin-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. |
