Molecular and Neuroanatomical Processes of Opioid addiction

阿片类药物成瘾的分子和神经解剖学过程

• 批准号: 10607297
• 负责人: Christopher M O'Brien
• 金额: $ 4.7万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607297
• 关键词: Absence of pain sensation; Acute Pain; Affective; Agonist; Anatomy; Anhedonia; Anxiety; Area; Automobile Driving; Behavior; Behavioral; Behavioral Model; Brain; Collaborations; Communities; Complex; Consummatory Behavior; Coupled; Data; Data Set; Development; Dimensions; Disease; Dose; Emotional; Environment; Equilibrium; Experimental Designs; Faculty; Fellowship; Female; Fentanyl; Foundations; Genetic; Glutamates; Goals; Grant; Habenula; Heterogeneity; Hyperactivity; Hypersensitivity; In Situ Hybridization; Individual; Individual Differences; Injections; Lateral; Literature; Measures; Mechanics; Mediating; Mental Depression; Mental disorders; Mentorship; Methodology; Modeling; Molecular; Mus; Negative Valence; Neuroanatomy; Neurons; Neurosciences; Nociception; Opiate Addiction; Opioid; Opioid Receptor; Output; Pain; Pathway interactions; Phenotype; Population; Predisposition; Prevalence; Prevention; Process; Psyche structure; Quantitative Reverse Transcriptase PCR; Recording of previous events; Rewards; Risk; Risk Factors; Rodent; Role; Shock; Stress; Stressful Event; Structure; Students; Substance Use Disorder; Substance abuse problem; Sucrose; Techniques; Testing; Training; United States National Institutes of Health; Vulnerable Populations; Work; addiction; behavior influence; behavior test; behavioral phenotyping; behavioral response; career; chronic pain; comorbidity; complex data; designer receptors exclusively activated by designer drugs; disease heterogeneity; foot; genetic manipulation; interest; kappa opioid receptors; mRNA Expression; male; member; molecular phenotype; motivated behavior; mu opioid receptors; neuromechanism; new therapeutic target; opioid abuse; opioid epidemic; opioid use; opioid use disorder; pain sensitivity; preference; receptor expression; response; reward processing; sex; skills; statistics; transcriptomics

Project Summary/Abstract Opioid use disorder is becoming more pervasive as the opioid epidemic continues. Opioids are heavily prescribed and are highly effective for treating acute pain, but not chronic pain, resulting in a large risk factor for abuse. The ability to predict specific individual susceptibility to opioid use disorder is limited, partially due to the complex comorbidity with other mental and physical illnesses. This requires a more extensive characterization that emphasizes innate individual differences in emotionality, pain sensitivity, and motivated behaviors. Recent work from the Barker lab has characterized these differences by using a stress model in rodents to give rise to these individual differences. These differences have been characterized through a behavioral battery targeting negative valence, pain, and opioid preference. Mice have different susceptibility profiles based on previous stressful experiences and mu-opioid receptors (MOR) within the lateral habenula (LHb) are candidates for this maladaptive plasticity. The proposed aims target these potential molecular pathways by using transcriptomics and testing the necessity of key anatomical structures using chemogenetic manipulation. Aim 1 will assess how MOR expression within the LHb changes in response to stress and across sexes. Beginning with behavioral testing, behavior profiles will be assessed, and MOR expression will be quantified using qRT-PCR and in situ hybridization. Dimension reduction analysis will be applied to these data sets to consolidate these parameters into opioid susceptibility profiles. Aim 2, will assess the necessity of the LHb in stress-mediated changes in opioid susceptibility. The LHb will be chemogenetically modulated via inhibitory DREADDs during foot shock and then characterization of opioid susceptibility will be performed through behavioral testing. The completion of these aims will establish potential molecular and anatomical targets for novel therapeutics as well as aid in the characterization of a translatable model of individualized opioid susceptibility. The proposed fellowship will provide the PI/trainee with a strong foundation for a career as an independent neuroscientist while providing a training environment in line with the goals of diversity in the NIH. The training incorporates ample professional development opportunities and strong faculty-student mentorships and collaborations. This will provide strong technical training in the domains of experimental design, behavior, molecular techniques, neuroanatomy, and statistics. Overall, this fellowship has significant potential to elucidate translatable phenotypes imperative to the treatment and prevention of opioid use disorder and provide the necessary training to become a valuable member of the addiction neuroscience community.

项目概要/摘要 随着阿片类药物流行的持续，阿片类药物使用障碍变得越来越普遍。阿片类药物含量很高 处方药对治疗急性疼痛非常有效，但对慢性疼痛无效，从而导致很大的危险因素 滥用。预测特定个体对阿片类药物使用障碍的易感性的能力有限，部分原因是 与其他精神和身体疾病的复杂合并症。这需要更广泛的 强调情感、疼痛敏感性和动机方面先天个体差异的表征 行为。巴克实验室最近的工作通过使用压力模型来描述这些差异 啮齿类动物造成这些个体差异。这些差异已通过 针对负价、疼痛和阿片类药物偏好的行为电池。小鼠有不同的易感性 基于先前的压力经历和外侧缰核内的μ阿片受体（MOR）的概况 (LHb) 是这种适应不良可塑性的候选者。拟议的目标针对这些潜在的分子 通过使用转录组学和使用化学遗传学测试关键解剖结构的必要性来确定途径 操纵。目标 1 将评估 LHb 内的 MOR 表达如何响应压力和变化而变化。 跨性别。从行为测试开始，将评估行为概况，并评估 MOR 表达 使用 qRT-PCR 和原位杂交进行定量。降维分析将应用于这些 数据集将这些参数整合到阿片类药物敏感性概况中。目标 2，将评估必要性 LHb 在应激介导的阿片类药物敏感性变化中的作用。 LHb 将通过化学遗传学调节 足部电击期间抑制性 DREADD，然后进行阿片类药物敏感性表征 通过行为测试。这些目标的完成将建立潜在的分子和解剖学 新疗法的目标以及帮助表征个体化的可翻译模型 阿片类药物敏感性。 拟议的奖学金将为 PI/实习生的职业生涯提供坚实的基础 独立的神经科学家，同时提供符合 NIH 多样性目标的培训环境。 培训包含充足的专业发展机会和强大的师生 指导和合作。这将为实验领域提供强有力的技术培训 设计、行为、分子技术、神经解剖学和统计学。总体而言，本次奖学金意义重大 阐明治疗和预防阿片类药物使用障碍所必需的可翻译表型的潜力 并提供必要的培训，成为成瘾神经科学界的有价值的成员。