Targeting the Ghrelin System for Novel Opioid Use Disorder Therapeutics

项目摘要 2019冠状病毒病（COVID-19）大流行在美国药物过量危机中爆发。 超过60%的药物过量与阿片类镇痛药有关，反复过量表明 阿片类药物使用障碍（OUD）的发展，这是一种不断增长和危及生命的医学状况。鉴于我们 目前，阿片类镇痛药不能将阿片类药物引起的疼痛缓解与阿片类药物滥用和OUD脱钩， 它们在医学上仍然是必不可少的，它们的使用可能会与新冠肺炎同时发生。阿片类药物一般 增强病毒复制、发病机制和感染性疾病进展，部分通过削弱免疫 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疾病有关。 系统（CNS）症状（例如，精神错乱、谵妄、烦躁不安），与一些患者中观察到的精神分裂症相一致。 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被证明， 是病毒发病机制和宿主脆弱性的函数，其中之一可能是慢性阿片类药物用于疼痛 管理和/或OUD。这些发现激发了迫切需要了解阿片类药物如何影响特定 宿主脆弱性因素和辅助因素，以及治疗新冠肺炎的药物如何影响阿片类信号传导， 特别是在控制阿片类药物的CNS作用的单细胞内。初步观察表明， 参与SARS-CoV-2细胞进入的基因在海洛因使用者的大脑中发生了改变。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表达与大鼠终生芬太尼摄入量有关， 这表明阿片类药物暴露可调节与Covid-19感染相关的宿主病毒进入和免疫功能。 鉴于并发的Covid-19和过量危机，阿片类药物在疼痛管理中的长期使用， OUD以及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 预测新冠肺炎的严重程度和阿片类药物暴露的OUD患者的适当治疗。基于 在此前提下，我们将检验以下假设，即男性从长期芬太尼自我给药中戒断 雌性大鼠将影响中枢神经系统中已鉴定的单细胞中介导SARS-CoV-2感染的关键靶点， 单核RNAseq转录组学（Aim 1）以及急性或慢性Covid-19候选药物将 改变阿片样物质的信号特征（例如，芬太尼、丁丙诺啡）在细胞系统中的作用（Aim 2）。我们期望 发现宿主病毒进入和免疫状态的改变标志物在鉴定的单个CNS细胞中， 慢性芬太尼自我给药，建立了在Covid-19中增强神经损伤的可能性 患者我们还希望证明Covid-19药物与阿片类信号之间的相互作用， 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病和进展的风险因素。

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.