Role of opioid receptor trafficking in tolerance and dependence

项目摘要 成瘾生物学中的一个基本问题是，为什么吗啡和海洛因等鸦片类生物碱药物有 当内啡肽和脑啡肽是天然的多肽配体时，诱发耐受和成瘾的可能性很高 对于阿片受体，不要这样做。在激动剂激活后，阿片受体受多个 机械装置。在这些调节机制中，阿片受体的快速内吞作用尤其令人感兴趣 因为它受多肽激动剂和生物碱类药物的不同调节。具体来说，内源性阿片类药物 多肽和某些阿片类药物如埃托啡和美沙酮刺激MU的快速内化 阿片受体。然而，吗啡强烈地激活受体信号，但不能刺激快速 Mu阿片受体的内化。此外，在内吞作用之后，单个受体可以被分选。 循环内切酶体和溶酶体间的区别。这种分选机制可以帮助受体 通过两种方式对细胞信号产生相反的调节作用。首先，内吞作用可以作为一种 受体再增敏的机制是将内化的受体从其所在位置运送到内吞体内 在完全活跃的状态下再循环到质膜上。其次，快速内部化可以作为第一步 通过将受体运送到内小体，从而实现受体下调 用于降解的溶酶体。因此，对于每个受体/配体对，必须同时评估内吞和 后内吞特性。我们已经产生了突变的MU阿片受体，内吞和后 内吞转运特性。在这里，我们建议利用这些突变受体来评估分子和 改变贩卖对耐受性、戒断和成瘾发展的行为影响。

Project Summary A fundamental question in addiction biology is why opiate alkaloid drugs such as morphine and heroin have a high liability for inducing tolerance and addiction while endorphins and enkephalins, the native peptide ligands for opioid receptors, do not. Following activation by agonists, opioid receptors are regulated by multiple mechanisms. Of these regulatory mechanisms, rapid endocytosis of opioid receptors is of particular interest because it is differentially regulated by peptide agonists and alkaloid drugs. Specifically, endogenous opioid peptides and certain opiate drugs such as etorphine and methadone stimulate the rapid internalization of mu opioid receptors. Morphine however, strongly activates receptor signaling but fails to stimulate the rapid internalization of mu opioid receptors. Furthermore, following endocytosis, individual receptors can be sorted differentially between recycling endosomes and lysosomes. This sorting mechanism can contribute to receptor regulation in two ways that have opposing effects on cell signaling. First, endocytosis can serve as a mechanism for receptor resensitization by delivering internalized receptors to endosomes from where they are recycled to the plasma membrane in a fully active state. Second, rapid internalization can serve as a first step toward receptor downregulation by delivering the receptors to endosomes from which they are sent to lysosomes for degradation. Hence for each receptor/ligand pair, one must evaluate both the endocytic and post-endocytic properties. We have generated mutant mu opioid receptors with altered endocytic and post- endocytic trafficking properties. Here we propose to utilize these mutant receptors to assess the molecular and behavioral effects of altered trafficking on the development of tolerance, withdrawal, and addiction.