The Opioid mesolimbic system in heroin abuse

海洛因滥用中的阿片类中脑边缘系统

• 批准号: 7799923
• 负责人: YASMIN L. HURD
• 金额: $ 47.58万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799923
• 关键词: AIDS/HIV problem; Alleles; Amygdaloid structure; Arrestins; Autopsy; Behavior; Brain; Brain region; Caucasians; Caucasoid Race; Cluster Analysis; Collection; Complex; Contracts; Corpus striatum structure; Coupled; Coupling; Crime; Data; Data Set; Development; Dimerization; Dinucleoside Phosphates; Disease; Drug abuse; Enkephalins; Event; Foundations; Functional disorder; Funding; GTP-Binding Proteins; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Load; Genetic Polymorphism; Genetic Transcription; Goals; Heroin; Heroin Abuse; Heterotrimeric GTP-Binding Proteins; Human; Individual; Investigation; Knowledge; Link; Mediating; Microarray Analysis; Molecular; Molecular Target; Moods; Morphine; Mutation; Neurobiology; Neurons; Neuropeptides; Nucleus Accumbens; Opiate Addiction; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Overdose; Oxycodone; Pathway Analysis; Pharmaceutical Preparations; Phase; Phosphorylation; Physiological; Population; Protein Analysis; Proteins; Public Health; RNA; Regulation; Regulatory Pathway; Research; Rewards; Risk; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Single Nucleotide Polymorphism; Structure; Study Subject; System; Time; Viral hepatitis; addiction; arrestin 2; base; cell growth regulation; drug of abuse; endogenous opioids; high risk; insight; mRNA Expression; mesolimbic system; mortality; mu opioid receptors; mutant; opioid abuse; prodynorphin; proenkephalin; protein function; public health relevance; receptor; receptor coupling; receptor density; receptor expression; trafficking

DESCRIPTION (provided by applicant): Heroin is a highly addictive drug and its abuse continues to be a major public health problem. Heroin abuse is associated with high mortality due to overdose, high risk of contracting diseases such as HIV/AIDS and viral hepatitis, and crime that often exceed that of most other abused drugs. Extensive research efforts have been dedicated to understanding the regulation of 5-opioid receptor (MOR), molecular target of heroin metabolites such as morphine, but limited studies have been conducted directly in the human brain regarding MOR and its intracellular signaling in relation to heroin abuse. Heroin abuse has a high genetic load and mutation of the MOR gene (OPMR1) has been linked with heroin abuse risk. During the first funding period for our studies, we documented that H 90% of subjects with the A118G mutation in our postmortem brain bank collection, from a homogenous Caucasian population, were heroin abusers. Neurobiological studies revealed that the polymorphism was relevant to opioid neuropeptide expression in the nucleus accumbens linked to reward and goal-directed behavior. Moreover, subjects with the 118G allele had higher functional coupling of the MOR in the nucleus accumbens. The proenkephalin (PENK) opioid neuropeptide is also strongly associated with reward and individuals with genetic polymorphism of this gene also had sensitized opioid receptor G-protein coupling in the nucleus accumbens. It is the aim of the next phase of our project to investigate more thoroughly the regulation of MOR; the intracellular G-protein signaling cascades that mediates the physiological actions of this receptor in heroin abusers and in relation to the OPMR1 polymorphism. Factors that modulate MOR function such as receptor density, phoshorylation state, dimerization with 4-opioid receptors, and coupling to 2-arrestin will be studied. Cluster and network analysis will be conducted on RNA data already collected from microarray analysis and customized real-time PCR datasets to identify the intracellular regulatory pathways linked to opioid receptor G-protein signaling. Key proteins within these networks will also be studied to validate the functional disturbances in relation to heroin use and the OPMR1 mutation. Expanding knowledge regarding MOR and its intracellular signaling machinery directly in the human brain will provide a major insight as to the neurobiological correlates linked with heroin abuse vulnerability and targets for medication development. PUBLIC HEALTH RELEVANCE: Heroin is a highly addictive drug and its abuse continues to be a major public health problem. Expanding knowledge regarding the regulation and function of mu opioid receptor, the target for heroin, directly in the human brain and in relation to genetic mutations will provide a major insight as to the neurobiological correlates linked with heroin abuse vulnerability. As such targeted for medications can be development.

描述（由申请人提供）：海洛因是一种高度成瘾的药物，其滥用仍然是一个主要的公共卫生问题。海洛因滥用与过量服用导致的高死亡率、感染艾滋病毒/艾滋病和病毒性肝炎等疾病的高风险以及往往超过大多数其他滥用药物的犯罪率有关。广泛的研究工作致力于了解 5-阿片受体 (MOR) 的调节，5-阿片受体 (MOR) 是吗啡等海洛因代谢物的分子靶标，但直接在人脑中进行的关于 MOR 及其与海洛因滥用相关的细胞内信号传导的研究有限。海洛因滥用具有很高的基因负荷，MOR 基因 (OPMR1) 的突变与海洛因滥用风险有关。在我们研究的第一个资助期间，我们记录到，在我们的死后脑库收集中，来自同质白人群体的 A118G 突变受试者中有 90% 是海洛因滥用者。神经生物学研究表明，该多态性与伏隔核中阿片类神经肽的表达有关，而伏隔核中的阿片类神经肽表达与奖励和目标导向行为相关。此外，具有 118G 等位基因的受试者在伏隔核中具有更高的 MOR 功能耦合。脑啡肽原 (PENK) 阿片类神经肽也与奖赏密切相关，具有该基因遗传多态性的个体在伏隔核中也具有致敏的阿片类受体 G 蛋白偶联。我们项目下一阶段的目标是更彻底地调查铁道部的监管情况；细胞内 G 蛋白信号级联介导海洛因滥用者中该受体的生理作用，并与 OPMR1 多态性相关。将研究调节 MOR 功能的因素，例如受体密度、磷酸化状态、与 4-阿片受体的二聚化以及与 2-arrestin 的偶联。将对从微阵列分析和定制的实时 PCR 数据集中收集的 RNA 数据进行聚类和网络分析，以确定与阿片受体 G 蛋白信号传导相关的细胞内调节途径。还将研究这些网络中的关键蛋白质，以验证与海洛因使用和 OPMR1 突变相关的功能障碍。扩展有关 MOR 及其直接在人脑中的细胞内信号传导机制的知识，将为了解与海洛因滥用脆弱性和药物开发目标相关的神经生物学相关性提供重要见解。公共卫生相关性：海洛因是一种高度成瘾的药物，其滥用仍然是一个主要的公共卫生问题。扩大有关 mu 阿片受体（海洛因的靶标）直接在人脑中的调节和功能以及与基因突变相关的知识，将为了解与海洛因滥用脆弱性相关的神经生物学相关性提供重要见解。因此可以开发针对药物。