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

摘要: Chronic morphine exposure upregulates adenylate cyclase signaling and reduces analgesic efficacy, a condition known as opioid tolerance. Nonopioid neurotransmitters can enhance tolerance, but the mechanism for this is poorly understood. We show that tolerance was delayed in mice lacking vasopressin 1b receptors (V1bRs) or after administration of V1bR antagonist into rostral ventromedial medulla, where transcripts V1bRs μ-opioid are co-localized. Vasopressin increased morphine-binding affinity cells expressing both receptors. Complex formation among V1bR, β-arrestin-2, receptor resulted vasopressin-mediated upregulation ERK phosphorylation sensitization. A leucine-rich segment C-terminus necessary association with β-arrestin-2. Deletion analgesia reduced These findings indicate inhibition μ-opioid-receptor-associated provides an approach enhancing without increasing