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: 10133034
• 负责人: Hannah Marie Stoveken
• 金额: $ 0.59万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133034
• 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; 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; Tail; Testing; Therapeutic; Ventral Striatum; Work; addiction; base; behavior test; beta-arrestin; desensitization; detection platform; 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.

项目摘要 /摘要 在过去的十年中，阿片类药物成瘾和意外过量已成为重大健康危机 随着这种高度上瘾的药物的普遍性和供应率显着增加。阿片类药物 是mu阿片受体（MOR）的激动剂，除了阻止疼痛信号传导外，还介导 发展不必要的副作用，包括容忍和持续使用，依赖性。莫 信号传导受受体下游的内源调节，以终止或调谐信号传导，因此 调节阿片类药物的生理作用。当前减少阿片类药物副作用的策略包括治疗 靶向 /调节已知的MOR调节剂（例如B- arrestin和G蛋白调节剂）的激活 信号传导（RGS）。尽管如此，还没有MOR监管机构的全面清单。使用公正的遗传屏幕，我们 最近发现了一个新型的孤儿G蛋白偶联受体（GPCR）信号传导途径 在两个独立的动物模型中展示了抗阿片类药物表型。此外，孤儿受体是共同的 与MOR一起在镇痛和奖励涉及的大脑关键区域中进行本地化。然而，这条新颖的道路以及如何 它可能调节MOR是完全不确定的。拟议的项目将检验孤儿GPCR的假设 途径是MOR的负调节剂，具有治疗潜力，可减轻阿片类药物的不良副作用。 为了检验该假设，将使用基于生物传感器的细胞测定来检查经典的MOR信号传导 以及如何通过孤儿GPCR途径的动态激活来改变它。另外，发出的信号传导 将从孤儿GPCR确定，以进一步发现信号通路如何内源相互作用。 最后，将在小鼠模型中确定孤儿GPCR降低阿片类药物副作用的能力 阿片类药物相关的行为。综上 找到临床用途来减少阿片类药物负相关的副作用。