Mapping brain-wide opioid actions by profiling neuronal activities and in vivo cellular target engagement

通过分析神经元活动和体内细胞靶标参与来绘制全脑阿片类药物作用

• 批准号: 10775623
• 负责人: Laura M. Bohn
• 金额: $ 83.99万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10775623
• 关键词: Affect; Affinity; Agonist; Architecture; Area; Atlases; Behavior; Binding; Binding Sites; Body part; Brain; Brain Mapping; Brain imaging; Brain region; Buprenorphine; Cells; Chemical Structure; Chemicals; Chemistry; Coupled; DNA; Data; Drug Targeting; FOS gene; Genes; Goals; Heterogeneity; Image; In Situ Hybridization; In Vitro; Individual; Ligands; Light; Link; Maps; Measures; Mediating; Molecular; Mus; Neurons; Opioid; Opioid Receptor; Overdose; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Proteins; Public Health; RNA; Research Personnel; Resolution; Salvia; Signal Transduction; Site; Somatotype; Specificity; Stains; Structure-Activity Relationship; Synthesis Chemistry; System; Techniques; Testing; Tissues; Validation; Visualization; Work; activity marker; addiction liability; biomarker identification; brain cell; cell type; cellular targeting; design; endogenous opioids; imaging approach; in situ imaging; in vivo; lead optimization; multimodality; neural; neuroregulation; new technology; off-target site; opioid use disorder; pain reduction; pharmacologic; preference; receptor; salvinorin A; screening; side effect; transcriptome; transcriptomics; Affect; Affinity; Agonist; Architecture; Area; Atlases; Behavior; Binding; Binding Sites; Body part; Brain; Brain Mapping; Brain imaging; Brain region; Buprenorphine; Cells; Chemical Structure; Chemicals; Chemistry; Coupled; DNA; Data; Drug Targeting; FOS gene; Genes; Goals; Heterogeneity; Image; In Situ Hybridization; In Vitro; Individual; Ligands; Light; Link; Maps; Measures; Mediating; Molecular; Mus; Neurons; Opioid; Opioid Receptor; Overdose; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Proteins; Public Health; RNA; Research Personnel; Resolution; Salvia; Signal Transduction; Site; Somatotype; Specificity; Stains; Structure-Activity Relationship; Synthesis Chemistry; System; Techniques; Testing; Tissues; Validation; Visualization; Work; activity marker; addiction liability; biomarker identification; brain cell; cell type; cellular targeting; design; endogenous opioids; imaging approach; in situ imaging; in vivo; lead optimization; multimodality; neural; neuroregulation; new technology; off-target site; opioid use disorder; pain reduction; pharmacologic; preference; receptor; salvinorin A; screening; side effect; transcriptome; transcriptomics

Abstract Opioids are highly effective at reducing pain, but their potential for addiction and overdose has led to a growing public health crisis. Researchers have attempted to develop new opioid compounds that are less likely to be abused and have fewer side effects, but these efforts have been difficult. The endogenous opioid system has multiple receptors and ligands heterogeneously expressed across different parts of the body and cell types. Tremendous work has been done to delineate the relationships between opioid receptors (ORs) and ligands. However, the specificity of ligand-receptor engagement often depends on relative affinities at predetermined targets. In general, in vivo spatial and cellular heterogeneity of the brain obscure opioid actions, making them hard to predict based on receptor affinity alone. Currently, single-cell and spatial transcriptomics are transforming our understanding of brain architecture. However, there is a significant gap in how we measure opioid actions and align them with the spatially resolved cellular atlas of the brain. Levering emerging CATCH and inverse activity marker (IAM) techniques, we propose multimodal profiling of opioid actions with spatial and single-cell resolution across the entire mouse brain. Using three pharmacologically diverse opioids, we aim to map neuronal activities and cellular binding of these drugs onto the entire mouse brain in an unbiased way and register them with cell types identified from single-cell transcriptomics. Furthermore, we will test whether a drug’s affinities across different ORs determine its in vivo cell and neural ensemble engagement. Not only would this project provide a circuit-level mechanism linking the molecular pharmacology to brain-wide opioid actions, but also lay out a roadmap for evaluating and developing new opioids, e.g., by incorporating regional and cell-type preference into the structure-activity-relationship for lead optimization or by revealing on- and off-target sites to guide further cell-type specific in vitro chemical screening and optimization.

抽象的 阿片类药物在减轻疼痛方面非常有效，但是它们的成瘾和过量的潜力导致了增长 公共卫生危机。研究人员试图开发新的阿片类化合物，这些化合物不太可能 受到虐待，副作用更少，但是这些努力很困难。内源性阿片类药物系统具有 多个接收器和配体在人体和细胞类型的不同部位异质表达。 已经做出了巨大的工作来描述阿片受体（ORS）和配体之间的关系。 但是，配体受体互动的特异性通常取决于预定的相对亲和力 目标。通常，大脑的体内空间和细胞异质性掩盖了阿片类药物的作用，使其成为 仅基于受体亲和力很难预测。 目前，单细胞和空间转录组学正在改变我们对大脑结构的理解。 但是，我们如何测量阿片类药物的作用并与空间解决方案保持一致 大脑的细胞地图集。杠杆式新兴捕获和反活动标记（IAM）技术，我们提出 整个小鼠大脑中具有空间和单细胞分辨率的阿片类药物作用的多模式分析。使用 三种药物多样的阿片类药物，我们旨在绘制这些药物的神经元活性和细胞结合 以公正的方式进入整个鼠标大脑，并用单细胞鉴定的细胞类型注册它们 转录组学。此外，我们将测试药物的亲和力是否在不同的OR中确定其体内 细胞和神经元合奏互动。该项目不仅会提供连接的电路级机制 分子药理学，用于整个大脑的阿片类药物，但也列出了评估和发展的路线图 新的阿片类药物，例如，通过将区域和细胞类型的偏好纳入结构性相关性，以实现 铅优化或通过揭示靶向和脱靶位点以引导进一步的细胞类型特异性体外化学化学物质 筛选和优化。