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

OPRM1偏向激动机制及体内后果的研究：Di

基本信息

批准号：
9126260
负责人：
PING-YEE LAW
金额：
$ 35.58万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9126260
关键词：
Addictive Behavior Address Adverse effects Affect Agonist Amygdaloid structure Brain Chronic Cocaine Corpus striatum structure Development Drug Addiction Drug Exposure Drug abuse Drug effect disorder Drug usage Electrophysiology (science)Ethanol Exhibits Extinction (Psychology)Family Fentanyl Foundations Future G-Protein-Coupled Receptors Genetic Transcription Heroin Hippocampus (Brain)Incentives Knock-in Mouse Learning Link Location Mediating Membrane Memory Messenger RNA MicroRNAs Molecular Molecular Conformation Morphine Morphology Motivation Neuronal Plasticity Neurons Nicotine Nucleus Accumbens Opiate Addiction Opiates Opioid Opioid Receptor Outcome Pain Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phosphorylation Phosphorylation Site Prefrontal Cortex Process Property Proteins Regulation Relapse Reporting Research Design Retrieval Rewards Role Signal Transduction Structure Substantia nigra structure Ventral Tegmental Area Writing addiction adult neurogenesis drug of abuse drug relapse drug reward experience in vivo interest long term memory neural circuit neurogenesis newborn neuron opioid use pleasure preference receptor response transcription factor

项目摘要

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.

描述（由申请人提供）：虽然阿片类药物可有效缓解短期疼痛，但长期使用这些药物仍然存在主要障碍。具体来说，许多副作用与药物有关，例如药物滥用事件的增加。导致成瘾，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长期药物暴露过程中通常与快乐、激励和学习有关的神经回路的激活和改变。腹侧从被盖区和黑质到伏隔核和纹状体，来自前额皮质、杏仁核和海马的谷氨酰胺能输入在慢性药物作用中也具有重要作用，因为海马是参与装饰性物质的储存、巩固和检索的结构。空间记忆和长期记忆，了解其在药物获取和复发以及药物奖励体验中的作用，已经变得越来越重要。此外，在药物暴露过程中观察到各种海马结构的形态可塑性，考虑到所有成瘾药物都已被证明会改变，新生神经元与海马内现有回路的整合可能会产生显着影响。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，将对我们研究过程中理解阿片类药物的长期使用产生重大影响。在μ-阿片受体 (OPRM1) 偏向激动，我们观察到吗啡和芬太尼这两种高度处方的阿片类药物对 microRNA-190 水平的调节存在差异，导致原代海马神经元培养物中 NeuroD 水平的差异，因为 NeuroD 是参与其中的转录因子。随着神经元的分化和成熟，我们发现OPRM1通过控制miR-190/NeuroD通路活性来调节海马体中的成体神经发生。由于吗啡和芬太尼都具有成瘾性，这两种激动剂对 miR-190/NeuroD 活性的差异控制并不参与成瘾行为的获得，而是参与与药物奖励相关的情境记忆的巩固和检索。，拟议的研究旨在：（A）了解吗啡和芬太尼偏向激动所涉及的分子机制，以便操纵这种偏向激动的结果；（B）确定miR-190/NeuroD 调节是海马成人神经发生的激动剂差异调节的核心；(C) 将 NeuroD 活动和神经发生的调节与阿片类激动剂诱导的条件性位置偏好的消失联系起来。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，并可以开发未来的治疗范例。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Morphine modulates mouse hippocampal progenitor cell lineages by upregulating miR-181a level.

DOI：
10.1002/stem.1774
发表时间：
2014-11
期刊：
STEM CELLS
影响因子：
5.2
作者：
Xu, Chi;Zhang, Yue;Zheng, Hui;Loh, Horace H.;Law, Ping-Yee
通讯作者：
Law, Ping-Yee

Morphine Promotes Astrocyte-Preferential Differentiation of Mouse Hippocampal Progenitor Cells via PKCε-Dependent ERK Activation and TRBP Phosphorylation.

DOI：
10.1002/stem.2055
发表时间：
2015-09
期刊：
Stem cells (Dayton, Ohio)
影响因子：
0
作者：
Xu C;Zheng H;Loh HH;Law PY
通讯作者：
Law PY

Neurod1 modulates opioid antinociceptive tolerance via two distinct mechanisms.

Neurod1 通过两种不同的机制调节阿片类镇痛药耐受性。

DOI：
10.1016/j.biopsych.2014.05.013
发表时间：
2014-11-15
期刊：
Biological psychiatry
影响因子：
10.6
作者：
Li W;He S;Zhou Y;Li Y;Hao J;Zhou X;Wang F;Zhang Y;Huang Z;Li Z;Loh HH;Law PY;Zheng H
通讯作者：
Zheng H

Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors.