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

描述（由申请人提供）：尽管阿片类药物对短期疼痛缓解有效，但长期使用这些药物仍然存在主要障碍。具体而言，与药物有关的许多副作用，例如导致成瘾的药物滥用事件不断增加，阻碍了阿片类药物的使用。一种可能的药物成瘾机制涉及在慢性药物暴露过程中，通常与愉悦、激励动机和学习有关的神经回路的激活和改变。除了腹侧被盖区和黑质向伏隔核和纹状体的多巴胺能输入外，前额皮质、杏仁核和海马的谷氨酰胺能输入也在慢性药物作用中起重要作用。由于海马体是与装饰性记忆、空间记忆和长期记忆的储存、巩固和检索有关的结构，因此了解其在药物获得和复发以及药物奖励体验中的作用变得非常重要。在药物暴露过程中，观察到海马不同结构的电生理和形态可塑性。此外，新生神经元与海马体内现有回路的整合可能对药物体验有显著影响。考虑到所有成瘾性药物都被证明会改变成人神经发生，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具体方面，将对理解阿片类药物的长期使用具有重要影响。在我们学习的过程中？我们观察到吗啡和芬太尼这两种高处方阿片类药物对microRNA-190水平的调节差异，导致初级海马神经元培养中NeuroD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/NeuroD通路活性，调节海马成体神经发生。我们进一步假设，由于吗啡和芬太尼都是成瘾性的，这两种激动剂对miR-190/NeuroD活性的差异控制与成瘾行为的习得无关，而是与药物奖励相关的情境记忆的巩固和检索有关。因此，拟开展的研究旨在：(A)了解吗啡和芬太尼偏倚激动作用的分子机制，从而操纵这种偏倚激动作用的结果；(B)确定miR-190/NeuroD调控是激动剂对海马成体神经发生差异调控的核心；(C)将NeuroD活动和神经发生的调节与阿片激动剂诱导的条件性位置偏好的消失联系起来。从这些研究中，我们预计，通过操纵miR-190/NeuroD通路活性，可以调节阿片类药物奖励体验的消失和随后的药物复发，并可以开发未来的治疗模式。

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 ?-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.