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.

项目总结/摘要 过去十年来，阿片类药物成瘾和意外过量已成为重大的健康危机 因为这类高度致瘾的药物的流行和可获得性急剧增加。阿片 是μ阿片受体（莫尔）的激动剂，其除了阻断疼痛信号传导外，还介导 产生不需要的副作用，包括耐受性和持续使用、依赖性。莫尔 信号传导在受体下游被内源性调节以终止或调节信号传导， 调节阿片类药物的生理效应。目前减少阿片类药物副作用的策略包括治疗 靶向/调节已知的莫尔调节剂如b-抑制蛋白和G蛋白调节剂的活化 信令（RGS）。不过，目前还没有一份全面的莫尔监管机构名单。使用无偏见的基因筛选，我们 最近发现了大脑中一种新的孤儿G蛋白偶联受体（GPCR）信号通路， 在两个独立的动物模型中证明了抗阿片样物质表型。此外，孤儿受体是共- 与莫尔一起定位于大脑中涉及镇痛和奖励的关键区域。然而，这种新的途径， 它可以调节莫尔，这是完全没有定义的。拟议的项目将检验孤儿GPCR 该通路是莫尔的负调节剂，具有减轻阿片类药物的不希望的副作用的治疗潜力。 为了验证这一假设，将采用基于生物传感器的细胞测定来检查经典的莫尔信号传导 以及它是如何通过孤儿GPCR途径的动态激活而改变的。此外，信号发射 从孤儿GPCR将被确定，以进一步揭示如何内源性相互作用的信号通路。 最后，孤儿GPCR降低阿片样物质副作用的能力将在小鼠模型中确定。 阿片类药物相关行为总之，这项工作将描绘一种新的抗阿片信号通路， 找到临床用途，以减少负面阿片类药物相关的副作用。