The effect of biased agonism at the Mu-Opioid receptor on drug seeking behavior

Mu-阿片受体的偏向激动对药物寻求行为的影响

• 批准号: 10590603
• 负责人: Lindsey Claire Felth
• 金额: $ 2.22万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590603
• 关键词: ARRB2; Absence of pain sensation; Adenylate Cyclase; Adverse event; Affect; Agonist; Analgesics; Animal Model; Animals; Arrestins; Automobile Driving; Bar Codes; Biological Assay; Biology; Cell model; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Clinic; Clinical; Codeine; Complex; Coupled; Cyclic AMP; Data; Dependence; Development; Dose; Drug Design; Drug Industry; Drug usage; Emergency Situation; Endocytosis; Endorphins; Engineering; Enkephalins; Failure; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glutamic Acid; Goals; Impulsivity; In Vitro; Knock-out; Knockout Mice; Ligands; Mediating; Methadone; Modeling; Morphine; Mus; Mutation; Neuronal Plasticity; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Oral; Overdose; Oxycodone; Pain; Pain management; Pathway interactions; Peptides; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Positioning Attribute; Property; Public Health; Recommendation; Recycling; Regulatory Pathway; Rewards; Risk; Self Administration; Signal Transduction; Signaling Protein; Substance Use Disorder; System; Testing; Threonine; Time; Titrations; Training; United States; Ventilatory Depression; Vicodin; Wild Type Mouse; abuse liability; behavioral plasticity; beta-Endorphin; clinical pain; desensitization; design; drug development; drug seeking behavior; emotional distress; endogenous opioids; in vivo; insight; knockout animal; mimetics; mouse model; mu opioid receptors; mutant; novel; opioid abuse; opioid epidemic; opioid overdose; opioid use; pre-clinical; prevent; protein activation; receptor; recruit; response; side effect; small molecule; trafficking

In 2020, drug overdoses jumped by 30% with 190 people in the United States dying every day from opioid overdose. Despite their significant risks, opioids analgesics, including morphine, codeine, Vicodin and oxycontin, are still regarded as the gold standard for alleviating severe pain. All of these drugs exert their analgesic effects through activation of a G protein coupled receptor (GPCR), specifically the Gi coupled µ- Opioid receptor (MOR). Repeated use of opioids leads to the development of tolerance to the analgesic effects of these drugs. This tolerance necessitates dose escalation to maintain sufficient pain control, which, in turn, increases both the likelihood of adverse events including enhanced respiratory depression and death as well as the liability to develop opioid dependence, manifested as physical and emotional distress in the absence of drug. Importantly, dependence is a key driver of the transition from opioid use to opioid abuse yet there is little understanding of the cellular signaling properties of the MOR that promote this transition. The signaling cascade induced by endogenous opioid ligands, such as beta-endorphin, from the MOR in response provide insight, as they produce analgesia without causing the severe tolerance and dependence observed in response to the small molecule opioid drugs. One key difference between the endogenous and exogenous opioids are their ability to recruit β-arrestin-2 following G-protein activation. Counter-intuitively, the endogenous ligands are better recruiters of β-arrestin-2 and subsequently drive substantially more receptor endocytosis and recycling than opioid drugs, even though they produce less tolerance. As such, we propose that facilitating endocytosis will titrate signal transduction at MOR, emulating endorphin signal transduction, thereby reducing tolerance and dependence. To test this hypothesis, we have manipulated the ‘phosphorylation barcode’ of MOR and created an engineered receptor that recruits β-arrestin-2 and undergoes endocytosis in response to morphine. Here we will thoroughly characterize this mutant receptor in a cell-based model, including a cell- based model of tolerance and dependence. We will also assess the phenotypes of WT and β-arrestin-2-KO mice in response to morphine and methadone, the only small molecule drug that significantly recruits β- arrestin-2. We will assess tolerance and dependence in β-arrestin-2-KO in response to morphine and more importantly, methadone. We will use a novel oral operant self-administration paradigm for 16 weeks to model the transition from impulsive to compulsive drug use in both WT and β-arrestin-2-KO animals. For decades the opioid field has focused, unsuccessfully, on developing drugs that show reduced side effects. We propose that these efforts have failed because they were based on the assumption that recruitment of β-arrestin-2 produces tolerance and dependence. The studies proposed here are designed to provide substantial evidence that recruitment of β-arrestin-2 and subsequent endocytosis and recycling is beneficial. As such, they could inform drug development of novel opioid with reduced abuse liability.

2020年，药物过量增加了30%，美国每天有190人死于阿片类药物