Studies on the the mechanism of OPRM1 biased agonism and in vivo consequences: Di

描述(申请人提供)：虽然阿片类药物对短期止痛有效，但长期使用这些药物仍然存在主要障碍。具体地说，与药物有关的许多副作用，如导致成瘾的药物滥用事件增加，阻碍了阿片类药物的使用。药物成瘾的一个可能机制涉及神经回路的激活和改变，在慢性药物暴露期间，神经回路通常涉及愉悦、激励动机和学习。除了从腹侧被盖区和黑质到伏隔核和纹状体的多巴胺能输入外，来自前额叶皮质、杏仁核和海马区的谷氨酸能输入也在慢性药物作用中发挥重要作用。由于海马体是参与装饰性记忆、空间记忆和长期记忆的存储、巩固和提取的结构，因此了解它在药物获得和复发以及药物奖励体验中的作用变得越来越重要。在药物暴露过程中，观察到不同的海马区结构在电生理和形态上的可塑性。此外，新生神经元与海马区现有回路的整合可能会对药物体验产生显著影响。考虑到所有成瘾药物都被证明可以改变成人的神经发生，阐明阿片类药物调节成人神经发生的机制，并确定成人神经发生参与的药物体验的特定方面，将对理解阿片类药物的长期使用具有重要影响。在我们对μ-阿片受体偏向激动剂的研究过程中，我们观察到吗啡和芬太尼这两种高处方阿片类药物对microRNA190水平的调节存在差异，导致原代海马神经元培养中神经元水平的差异。由于NeuroD是参与神经元分化和成熟的转录因子，我们假设OPRM1通过控制miR-190/Neurd途径的活性来调节成年神经元在海马区的发生。我们进一步假设，由于吗啡和芬太尼都是成瘾的，这两种激动剂对miR-190/NeuD活性的不同控制并不涉及成瘾行为的获得，而是与药物奖赏相关的上下文记忆的巩固和提取有关。因此，拟议的研究旨在：(A)了解吗啡和芬太尼偏向激动剂参与的分子机制，以操纵这种偏向激动剂的结果；(B)确定miR-190/Neurd调控是激动剂对成年海马神经发生的不同调控的核心；以及(C)将神经D活动和神经发生的调控与阿片类激动剂诱导的条件性位置偏爱的消退联系起来。从这些研究中，我们预计，通过操纵miR-190/NeurD通路的活性，阿片类药物奖励经验的消失和随后的药物复发可以得到调节，并可以开发出未来的治疗范例。

DESCRIPTION (provided by applicant): Although opioid drugs are effective for short-term pain relief, major obstacles remain with long-term use of these drugs. Specifically, the many side effects are associated with the drugs, such as increasing incidents of drug abuse leading to addiction, have hampered opioid drug usage. A probable mechanism for drug addiction involves the activation and alteration in the neural circuitry that normally is involved in pleasure, incentive motivation, and learning, during chronic drug exposure. In addition to dopaminergic inputs from the ventral tegmental area and substantia nigra to the nucleus accumbens and striatum, glutaminergic inputs from the prefrontal cortex, amygdala, and hippocampus also have important roles in chronic drug action. Since the hippocampus is the structure involved in the storage, consolidation, and retrieval of decorative, spatial, and long-term memory, understanding its roles in drug acquisition and relapse, as well as drug reward experiences, has gained importance. Both electrophysiological and morphological plasticity have been observed with the various hippocampal structures during the course of drug exposure. In addition, integration of newborn neurons to the existing circuit within the hippocampus may have pronounced effects on the drug experience. Considering that all addictive drugs have been shown to alter adult neurogenesis, elucidating the mechanism by which opioid drugs regulate adult neurogenesis, and identifying the specific aspect of the drug experience that adult neurogenesis participates in will have a significant impact in understanding the long-term use of opioid drugs. During the course of our studies on μ-opioid receptor (OPRM1) biased agonism, we observed that morphine and fentanyl, two highly prescribed opioids, regulate the microRNA-190 level differentially, leading to differences in NeuroD levels within primary hippocampal neuron cultures. Since NeuroD is the transcription factor involved in differentiation and maturation of neurons, we hypothesize that OPRM1, by controlling miR-190/NeuroD pathway activity, regulates adult neurogenesis in the hippocampus. We further hypothesize that, since morphine and fentanyl are both addictive, differential control of miR-190/NeuroD activity by these two agonists is not involved in the acquisition of addictive behavior, but rather in the consolidation and retrieval of the context memory associated with drug reward. Therefore, the proposed studies are designed: (A) to understand the molecular mechanism involved in morphine and fentanyl biased agonism so as to manipulate the outcomes of this biased agonism; (B) to establish that miR-190/NeuroD regulation is central to the agonists differential regulation of adult neurogenesis in the hippocampus; and (C) to link the regulation of NeuroD activities and neurogenesis with the extinction of conditioned place preference induced by opiate agonists. From these studies, we anticipate that, by manipulating the miR-190/NeuroD pathway activity, the extinction of the opioid drug reward experience and subsequent drug relapse, can be regulated, and a future treatment paradigm can be developed.