Targeting the Ghrelin System for Novel Opioid Use Disorder Therapeutics

针对新型阿片类药物使用障碍治疗的 Ghrelin 系统

• 批准号: 10168769
• 负责人: Kathryn A. Cunningham
• 金额: $ 23.74万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10168769
• 关键词: 2019-nCoV; Acute; Administrative Supplement; Affect; Astrocytes; Blood; Blood Platelets; Brain; Brain region; Buprenorphine; COVID-19; COVID-19 pandemic; Cell Line; Cell Nucleus; Cell model; Cells; Chronic; Clinical Trials; Communicable Diseases; Communication; Confusion; Delirium; Development; Disease Progression; Drug Interactions; Erythrocytes; Female; Fentanyl; Goals; Heroin Users; Heterogeneity; Immune; Immune system; Infection; Intake; Integration Host Factors; Leukocytes; Life; Link; Mediating; Medical; Medicine; Microglia; Molecular; Nervous System Trauma; Neuraxis; Neuroimmune; Neurons; Opioid; Opioid Analgesics; Overdose; Pain management; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Rattus; Reporting; Research; Risk Factors; SARS coronavirus; Self Administration; Severity of illness; Signal Transduction; Surface; Symptoms; Synapses; System; Testing; Therapeutic; Tissues; Viral; Viral Pathogenesis; Virus; Virus Receptors; Virus Replication; Withdrawal; base; chemokine; cofactor; comorbidity; cytokine; dysphoria; ghrelin; illicit opioid; immune function; immunological status; immunopathology; in vitro Model; in vivo; innovation; male; novel; opioid abuse; opioid exposure; opioid overdose; opioid use; opioid use disorder; pain relief; prescription opioid; response; symptomatology; therapeutic development; transcriptome sequencing; transcriptomics

PROJECT SUMMARY The coronavirus disease 2019 (Covid-19) pandemic erupted into the midst of the drug overdose crisis in the US. Over 60% of drug overdoses are linked to opioid analgesics, with repeated overdoses indicative of the development of opioid use disorder (OUD), a growing and life-threatening medical condition. Given that we are unable to decouple opioid-induced pain relief from opioid abuse and OUD at present, opioid analgesics will remain essential in medicine and their use is likely to co-occur with Covid-19 illness. Opioid medications generally enhance viral replication, pathogenesis, and infectious disease progression, in part via weakening the immune system. The SARS-CoV-1 virus is neuroinvasive and neurovirulent and is linked to progressive central nervous system (CNS) symptoms (e.g., confusion, delirium, dysphoria), aligning with symptomatology seen in some Covid-19 patients. As for other viruses, SARS-CoV-2 immunopathology and disease progression will prove to be a function of virus pathogenesis and host vulnerability, one of which may be chronic opioid use in pain management and/or OUD. These findings inspire the urgent need to understand how opioids impact specific host vulnerability factors and cofactors, and how medications proposed to treat Covid-19 affect opioid signaling, particularly within single cells that control CNS actions of opioids. Initial observations suggest that host factors involved in SARS-CoV-2 cellular entry are altered in the brains of heroin users. We recently reported that brain- region specific expression of immune cytokines and chemokines tracks with lifetime fentanyl intake in rats, suggesting that opioid exposure regulates host viral entry and immune function relevant to Covid-19 infection. Given the concurrent Covid-19 and overdose crises, the chronic use of opioids in pain management, the growing problem of OUD as well as illegal abuse of opioid drugs, we propose two specific aims of immediate relevance to predicting Covid-19 disease severity and appropriate therapeutics in opioid-exposed OUD patients. Based upon this premise, we will test the hypothesis that withdrawal from chronic fentanyl self-administration in male and female rats will impact key targets that mediate SARS-CoV-2 infection in identified single cells in CNS via single-nuclei RNAseq transcriptomics (Aim 1) and that acute or chronic Covid-19 medication candidates will alter signaling profiles of opioids (e.g., fentanyl, buprenorphine) in a cellular system (Aim 2). We expect to discover altered markers of host viral entry and immunological status in identified single CNS cells following chronic fentanyl self-administration, establishing the potential for enhanced neurological damage in Covid-19 patients. We also expect to demonstrate interactions between Covid-19 medications and opioid signaling which predict potential interactions in vivo. These innovative aims are consistent with the goals of NOT-DA-20-047 to determine if opioid exposure is a risk factor for the onset and progression of Covid-19.

项目总结 冠状病毒病2019年(新冠肺炎)大流行在美国爆发药物过量危机。 超过60%的药物过量与阿片类镇痛剂有关，反复过量表明 阿片类药物使用障碍(OUD)的发展，这是一种日益增长的威胁生命的医疗条件。鉴于我们是 无法将阿片类药物引起的疼痛缓解与阿片类药物滥用脱钩，目前，阿片类止痛药将 在医学上仍然是必不可少的，它们的使用很可能与新冠肺炎疾病同时发生。阿片类药物一般 增强病毒复制、致病机制和传染病进展，部分是通过削弱免疫 系统。SARS-CoV-1病毒具有神经侵袭性和神经毒性，与进行性中枢神经系统有关 神经系统(CNS)症状(例如，神志不清、神志不清、烦躁不安)，与某些 新冠肺炎患者。至于其他病毒，SARS-CoV-2的免疫病理学和疾病进展将证明 是病毒发病机制和宿主脆弱性的函数，其中之一可能是在疼痛中长期使用阿片类药物 管理和/或OUD。这些发现激发了人们迫切需要了解阿片类药物如何影响特定的 宿主易感性因素和辅助因素，以及拟用于治疗新冠肺炎的药物如何影响阿片信号转导， 尤其是在控制阿片类药物中枢神经系统活动的单个细胞内。初步观察表明，宿主因素 参与SARS-CoV-2细胞进入的海洛因吸毒者的大脑发生了变化。我们最近报道了大脑- 免疫细胞因子和趋化因子的区域特异性fic表达与大鼠终生芬太尼摄入量的关系 提示阿片类药物暴露调节宿主病毒进入和新冠肺炎感染相关的免疫功能。 鉴于同时存在的新冠肺炎和过量用药危机，在疼痛管理中长期使用阿片类药物，越来越多的 对于滥用和非法滥用阿片类药物的问题，我们提出了两个直接相关的具体目标 目的：预测阿片类药物暴露患者新冠肺炎的严重程度和适当的治疗方法。基座 在这一前提下，我们将检验男性患者停止长期服用芬太尼的假设 雌性大鼠将通过影响中枢神经系统中已确定的单个细胞中介导SARS-CoV-2感染的关键靶点 单核RNAseq转录组学(目标1)和急性或慢性新冠肺炎候选药物将 改变细胞系统中阿片类药物(如芬太尼、丁丙诺啡)的信号特征(目标2)。我们希望 在已鉴定的单个中枢神经系统细胞中发现宿主病毒进入和免疫状态的改变标志 慢性芬太尼自我给药建立了新冠肺炎增加神经损害的可能性 病人。我们还希望展示新冠肺炎药物与阿片类药物之间的相互作用 预测体内潜在的相互作用。这些创新目标与NOT-DA-20-047的目标一致 确定阿片类药物暴露是否是新冠肺炎发生和发展的危险因素。