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

描述（由申请人提供）：虽然阿片类药物对短期疼痛缓解有效，但长期使用这些药物仍存在主要障碍。具体而言，许多副作用与药物有关，例如药物滥用导致成瘾的事件增加，阻碍了阿片类药物的使用。药物成瘾的一个可能机制涉及在慢性药物暴露期间，通常涉及快乐、激励动机和学习的神经回路的激活和改变。除了从腹侧被盖区和黑质到中脑核和纹状体的多巴胺能输入外，来自前额皮质、杏仁核和海马的多巴胺能输入在慢性药物作用中也具有重要作用。由于海马体是涉及装饰性、空间性和长期记忆的存储、巩固和检索的结构，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，观察到各种海马结构的电生理和形态可塑性。此外，新生神经元与海马内现有回路的整合可能对药物体验产生显著影响。考虑到所有成瘾性药物已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产生重大影响。在我们对μ-阿片受体（OPRM 1）偏向激动作用的研究过程中，我们观察到吗啡和芬太尼（两种高度处方的阿片类药物）对microRNA-190水平的调节差异，导致原代海马神经元培养物中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，因此我们假设OPRM 1通过控制miR-190/NeuroD通路活性来调节海马中的成年神经发生。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活性的差异控制不参与成瘾行为的获得，而是参与与药物奖励相关的背景记忆的巩固和恢复。因此，所提出的研究被设计为：（A）理解吗啡和芬太尼偏向激动作用中涉及的分子机制，以便操纵这种偏向激动作用的结果;（B）确定miR-190/NeuroD调节是海马中成人神经发生的激动剂差异调节的中心;和（C）将NeuroD活性和神经发生的调节与阿片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/NeuroD通路活性，可以调节阿片类药物奖赏体验的消失和随后的药物复发，并且可以开发未来的治疗范例。

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.