阿片类镇痛药等引起的耐受和依赖一直是困扰其临床应用的一个重要问题。近年发现，根据阿片类药物激活μ阿片受体（MOR）后引起受体行为改变的不同可将其分为两类，即非偏爱型和偏爱型激动剂。前者与内源性阿片肽类似，在激活MOR发挥药理作用同时，诱发内吞和转运，仅引起较弱的耐受和依赖；后者激活MOR后，不能有效诱发MOR的内吞和转运，引起较强的耐受和依赖，提示MOR转运可能与阿片功能相关。咪唑啉受体候选蛋白IRAS是本课题组发现的与MOR具有相互作用的蛋白，调节非偏爱型激动剂引起的MOR转运并改善其功能。然而，IRAS是否对于偏爱型激动剂（吗啡）作用下的MOR也具有调节作用尚不清楚。本研究拟利用IRAS敲除和基因改造RMOR等模式动物，研究IRAS通过调节MOR转运对吗啡的镇痛和耐受、依赖作用及可能的分子机制，为阐明阿片类药物耐受、成瘾的神经生物学机制，寻找有效治疗策略奠定基础。

Opioid tolerance and dependence is always a big issue in the clinic. Recently, opioid drugs were classified into unbiased and biased agonist based on the difference of μ opioid receptor (MOR) trafficking properties. Unbiased MOR agonist stimulates MOR and induces the receptor endocytosis and trafficking in vitro, and produces analgesia with less side effects in vivo; while biased MOR agonist fails to promote MOR trafficking, and therefore causes severe tolerance and dependence. We recently found imidazoline receptor antisera-selected (IRAS) is new protein interacting with MOR. It could modulate unbiased MOR agonist-induced MOR trafficking and the following functions. However, whether IRAS has the regulatory effect on MOR stimulated by biased agonist morphine is remained unknown. To answer the question, we would study the effect of IRAS on morphine-induced analgesia, tolerance and dependence and the underlying mechanism of IRAS regulating MOR trafficking by taking advantage of IRAS knockout and gene modified RMOR mouse. The study would supply a basis for clarifying the mechanism of opioid function and seeking cure strategy of anti-opioid addiction.