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