Investigating New Roles for Orphan GPCRs in Opioid Actions

研究孤儿 GPCR 在阿片类药物作用中的新作用

• 批准号: 9900565
• 负责人: Hannah Marie Stoveken
• 金额: $ 6.74万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900565
• 关键词: Ablation; Absence of pain sensation; Adenylate Cyclase; Affinity; Agonist; American; Analgesics; Animal Model; Area; Arrestins; Behavior; Binding; Bioavailable; Biological Assay; Biosensor; Brain; Cell Surface Receptors; Cells; Cellular Assay; Clinical; Coupling; Cultured Cells; Cyclic AMP; Dependence; Detection; Development; Divorce; Evaluation; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Generations; Genetic; Genetic Screening; Habenula; Health; Heterotrimeric GTP-Binding Proteins; Heterozygote; In Vitro; Kinetics; Knockout Mice; Ligands; Measures; Medial; Mediating; Medication Management; Motor Activity; Mus; Nociception; Opiate Addiction; Opioid; Opioid agonist; Oral; Orphan; Output; Overdose; Pain; Pain management; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Prevalence; Promega; Property; Publishing; Rattus; Receptor Activation; Receptor Signaling; Regulation; Reporter Genes; Rewards; Role; Signal Pathway; Signal Transduction; Signaling Protein; System; Tail; Testing; Therapeutic; Ventral Striatum; Work; addiction; base; behavior test; beta-arrestin; desensitization; heroin overdose; high throughput screening; in vivo; inward rectifier potassium channel; mouse model; mu opioid receptors; nano; novel; opiate tolerance; opioid overdose; pain relief; pain signal; prescription opioid; receptor; receptor expression; recruit; response; side effect; small molecule; therapeutic target; trafficking

Project Summary / Abstract Opioid addiction and accidental overdose have emerged as significant health crises in the last decade as the prevalence and availability of this highly addicting class of drugs have dramatically increased. Opioids are agonists for the mu opioid receptor (MOR), which in addition to blocking pain signaling, also mediates the development of unwanted side effects including tolerance and with continued usage, dependence. MOR signaling is endogenously regulated downstream of the receptor to terminate or tune signaling and to thus modulate the physiological effects of opioids. Current strategies to curtail opioid side effects include therapeutic targeting / modulating activation of known MOR regulators such as b-arrestin and regulators of G protein signaling (RGS). Still, there is no comprehensive list of MOR regulators. Using an unbiased genetic screen, we recently uncovered a novel orphan G protein-coupled receptor (GPCR) signaling pathway in the brain that demonstrates an anti-opioid phenotype in two independent animal models. Further, the orphan receptor is co- localized with MOR in key areas of the brain involved in analgesia and reward. Yet, this novel pathway and how it may regulate MOR is wholly undefined. The proposed project will test the hypothesis that the orphan GPCR pathway is a negative regulator of MOR with therapeutic potential to mitigate the unwanted side effects of opioids. To test this hypothesis, biosensor-based cellular assays will be employed to examine classical MOR signaling and how it is altered by dynamic activation of the orphan GPCR pathway. Additionally, the signaling emanating from the orphan GPCR will be determined to further uncover how the signaling pathways endogenously interact. Finally, the ability of the orphan GPCR to decrease opioid side effects will be determined in mouse models of opioid-related behaviors. Taken together, this work will delineate a novel anti-opioid signaling pathway that could find clinical use to lessen negative opioid-related side effects.

项目概要/摘要 在过去十年中，阿片类药物成瘾和意外过量已成为严重的健康危机 因为这类高度成瘾的药物的流行率和可用性急剧增加。阿片类药物 是 mu 阿片受体 (MOR) 的激动剂，除了阻断疼痛信号传导外，还介导 产生不良副作用，包括耐受性和持续使用、依赖性。铁道部 信号传导在受体下游受到内源性调节，以终止或调整信号传导，从而 调节阿片类药物的生理作用。目前减少阿片类药物副作用的策略包括治疗 靶向/调节已知 MOR 调节因子的激活，例如 b-arrestin 和 G 蛋白调节因子 信令（RGS）。尽管如此，铁道部监管机构仍没有完整的名单。使用公正的基因筛查，我们 最近在大脑中发现了一种新的孤儿 G 蛋白偶联受体 (GPCR) 信号通路 在两个独立的动物模型中展示了抗阿片类药物表型。此外，孤儿受体是共- MOR 定位于大脑中涉及镇痛和奖赏的关键区域。然而，这种新颖的途径以及如何 它可能会监管 MOR 完全未定义。拟议的项目将测试孤儿 GPCR 的假设 途径是 MOR 的负调节因子，具有减轻阿片类药物不良副作用的治疗潜力。 为了检验这一假设，将采用基于生物传感器的细胞测定来检查经典的 MOR 信号传导 以及孤儿 GPCR 通路的动态激活如何改变它。此外，发出的信号 来自孤儿 GPCR 的信号将被确定，以进一步揭示信号通路如何内源性相互作用。 最后，将在小鼠模型中确定孤儿 GPCR 减少阿片类药物副作用的能力 阿片类药物相关行为。总而言之，这项工作将描绘出一种新型的抗阿片类药物信号通路，该通路可以 寻找临床用途来减少阿片类药物相关的副作用。