Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway. Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway

Regulator of G protein signaling z1 (RGSz1), a member of the RGS family of proteins, is present in several networks expressing mu opioid receptors (MOPR). By using genetic mouse models for global or brain region-targeted manipulations of RGSz1 expression, we demonstrate that the suppression of RGSz1 function increases the analgesic efficacy of MOPR agonists in male and female mice and delays the development of morphine tolerance while decreasing the sensitivity to rewarding and locomotor activating effects. Using biochemical assays and next-generation RNA sequencing, we identified a key role of RGSz1 in the periaqueductal gray (PAG) in morphine tolerance. Chronic morphine administration promotes RGSz1 activity in the PAG, which in turn modulates transcription mediated by the Wnt/β-catenin signaling pathway to promote analgesic tolerance to morphine. Conversely, the suppression of RGSz1 function stabilizes Axin2-Gaz complexes near the membrane and promotes β-catenin activation, thereby delaying the development of analgesic tolerance. These data show that the regulation of RGS complexes, particularly those involving RGSz1-Gaz, represents a promising target for optimizing the analgesic actions of opioids without increasing the risk of dependence or addiction. Overall design: Understanding the impact of morphine tolerance and the influence of RGSz1 on gene expression in the PAG

G蛋白信号调节因子z1（Regulator of G protein signaling z1，RGSz1）是RGS蛋白家族（RGS family of proteins）的成员，在表达μ阿片受体（mu opioid receptors，MOPR）的多种神经环路中均有分布。本研究采用用于RGSz1表达全身性或脑区靶向性调控的遗传工程小鼠模型，证实抑制RGSz1功能可提升雌雄小鼠体内MOPR激动剂的镇痛效能，延缓吗啡耐受的发生，并降低其奖赏效应与运动激活效应的敏感性。通过生化实验与下一代RNA测序（next-generation RNA sequencing），我们明确了中脑导水管周围灰质（periaqueductal gray，PAG）内的RGSz1在吗啡耐受进程中的关键调控作用。慢性吗啡给药可增强PAG内RGSz1的活性，进而调控Wnt/β-连环蛋白信号通路（Wnt/β-catenin signaling pathway）介导的转录过程，最终促进吗啡镇痛耐受的形成。反之，抑制RGSz1功能可稳定细胞膜附近的Axin2-Gaz复合物，并促进β-连环蛋白的激活，从而延缓镇痛耐受的发生发展。上述研究数据表明，调控RGS复合物——尤其是涉及RGSz1-Gaz的复合物——可作为优化阿片类药物镇痛效果、同时降低依赖与成瘾风险的极具潜力的治疗靶点。本研究整体设计旨在阐明吗啡耐受的发生机制，以及RGSz1对PAG内基因表达的调控作用。