Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids
Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids
复制标题
新型诱导剂激活自噬可防止 BECN2 介导的大麻素药物耐受
DOI：
10.1080/15548627.2016.1187367
复制
发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
He, Congcong
中科院分区：
文献类型：
--
作者：
Kuramoto, Kenta;Wang, Nan;He, Congcong
大麻素和相关药物通过激活CNR 1（大麻素受体1 [大脑]）产生深刻的行为效应（如镇痛作用）。然而，重复给予大麻素会引发受体的溶酶体降解和药物耐受性的快速发展，限制了大麻在慢性疾病中的医疗用途。大麻素耐受性的致病机制尚未完全了解，对其预防知之甚少。在这里，我们表明，参与大自噬/自噬（一种保守的溶酶体降解途径），BECN 2（Beclin 2），介导大麻素耐受性，通过防止CNR 1回收和再敏化后，长期激动剂暴露，和Becn 2的删除救援CNR 1活性在小鼠大脑中，并传达耐镇痛耐受慢性大麻素。为了在治疗上靶向BECN 2，我们建立了BECN 2的竞争性募集模型，并鉴定了新的合成的、天然的或生理的自噬刺激物，这些刺激物使BECN 2与GPRASP 1结合，GPRASP 1是CNR 1降解的受体蛋白。这些自噬诱导剂的共同施用有效地恢复了大脑CNR 1的水平和信号传导，并保护小鼠对重复使用大麻素产生耐受性。总的来说，我们的研究结果证明了自噬，受体信号传导和精神活性药物调节的动物行为之间的功能联系，并开发了一种新的策略，通过调节BECN 2相互作用组和自噬活性来预防耐受性和提高大麻素的医疗功效。
Cannabinoids and related drugs generate profound behavioral effects (such as analgesic effects) through activating CNR1 (cannabinoid receptor 1 [brain]). However, repeated cannabinoid administration triggers lysosomal degradation of the receptor and rapid development of drug tolerance, limiting the medical use of marijuana in chronic diseases. The pathogenic mechanisms of cannabinoid tolerance are not fully understood, and little is known about its prevention. Here we show that a protein involved in macroautophagy/autophagy (a conserved lysosomal degradation pathway), BECN2 (beclin 2), mediates cannabinoid tolerance by preventing CNR1 recycling and resensitization after prolonged agonist exposure, and deletion of Becn2 rescues CNR1 activity in mouse brain and conveys resistance to analgesic tolerance to chronic cannabinoids. To target BECN2 therapeutically, we established a competitive recruitment model of BECN2 and identified novel synthetic, natural or physiological stimuli of autophagy that sequester BECN2 from its binding with GPRASP1, a receptor protein for CNR1 degradation. Co-administration of these autophagy inducers effectively restores the level and signaling of brain CNR1 and protects mice from developing tolerance to repeated cannabinoid usage. Overall, our findings demonstrate the functional link among autophagy, receptor signaling and animal behavior regulated by psychoactive drugs, and develop a new strategy to prevent tolerance and improve medical efficacy of cannabinoids by modulating the BECN2 interactome and autophagy activity.