Preserving opioid analgesia using a novel adenosinergic approach

 描述(申请人提供)：阿片类药物用于长期治疗慢性疼痛受限于相对较差的疗效和出现适应性中枢神经系统变化，从而导致止痛耐受，增加疼痛(阿片类药物诱导的超敏反应，OIH)和身体依赖，抵消镇痛，构成健康负担，并造成社区滥用责任。1-9我们现在首次通过A3 GPCR亚型，腺苷受体(A3AR)及其腺苷激酶(ADK)控制的腺苷神经调节功能障碍，在止痛耐受，OIH和依赖中受到阿片类药物的限制。这项建议强调了一个多学科的研究计划，旨在探索ADK到A3AR轴的贡献&A3AR激动剂的适用范围，同时调查其潜在的保护机制(S)和中枢神经系统的作用部位。值得注意的是，A3AR激动剂，如IB-MECA及其2-氯类似物(CL-IB-MECA)，已作为新型抗炎和抗癌药物进入II/III期临床试验，具有良好的安全性。10-13在目标1中，我们将研究ADK(及其酶活性)和A3AR在SC胶质细胞和神经元中的时间和细胞表达(免疫荧光和遗传/蛋白质组分析)。同时，腰椎穿刺液和脑脊液中的嘌呤核苷浓度将通过有针对性的代谢方法进行测量。我们将(1)通过剂量-反应曲线和时间进程研究以及性别对A3AR效应的影响来表征A3AR激动剂的药理学特征；(2)考察SC作为作用部位的贡献。作为推论，我们将通过测试氧化密码子和A3AR激动剂来探索研究结果的临床普适性，并检查延髓头端腹内侧(RVM)作为额外作用部位的作用。在目标2中，为了收集A3AR激动剂如何提供保护的机械性理解，我们将开始在SC背角水平参与的信号通路的初步探索。为此，我们将使用蛋白质组学分析来研究A3AR激动剂的有益效果是否至少部分是通过抑制GSK3？和P2X7R-炎症小体途径来驱动的，该途径控制IL-1？和神经炎症。我们还将评估这些效应是否与IL-10表达和功能增加而从促炎状态转变为抗炎状态有关。我们希望我们的结果为新的阿片类药物不良副作用的治疗提供强有力的科学基础，这些副作用基于选择性的A3AR靶向治疗来反调节阿片类药物的止痛，同时评估已经在临床试验中的A3AR激动剂的翻译影响的可能性。A3AR的选择性激活不仅将改变目前治疗慢性疼痛的方法，而且可能有利于由于腺苷稳态(即滥用药物病理)的放松而导致的其他疾病。14该项目非常适合CEBRA方案，因为它通过测试一个缺乏信息的高度新颖和重要的假设来实现其目标，如果得到证实，将对这一领域的当前思维产生重大影响。

 DESCRIPTION (provided by applicant): Opioid use for the long-term treatment of chronic pain is limited by relatively poor efficacy & the emergence of adaptive CNS changes that result in analgesic tolerance, increase pain (opioid-induced hypersensitivity, OIH) & physical dependence that offset analgesia, pose a health burden & create community abuse liability.1-9 We now implicate for the first time opioid-induced dysfunction in adenosine neuromodulation via the A3 GPCR subtype, adenosine receptor (A3AR) & its control by adenosine kinase (AdK) in analgesic tolerance, OIH, & dependence. This proposal highlights a multidisciplinary research plan aimed at exploring the contribution of the AdK-to-A3AR axis & the breadth of A3AR agonist applicability while investigating its underlying protective mechanism(s) & sites of action in the CNS. Noteworthy, A3AR agonists, such as IB-MECA & its 2-chloro analogue (Cl-IB-MECA), have advanced to Phase II/III clinical trials as novel anti-inflammatory & anticancer agents with good safety profiles.10-13 In Aim 1, we will investigate the temporal & cellular expression of AdK (& its enzymatic activity) & A3AR in SC glia & neurons (immunofluorescence & genetic/proteomic analysis). In parallel, purine nucleoside concentrations in SC & CSF (from lumbar puncture) will be measured by targeted metabolic approaches. We will (1) characterize the pharmacological profile of A3AR agonists via dose- response curves & time course studies as well as effect of gender on A3AR effects & (2) examine the contribution of the SC as a site of action. As a corollary, we will explore the clinical generalization of findings by testing oxycodon & A3AR agonists & examine the contribution of the rostral ventromedial medulla (RVM), as an additional site of action. In Aim 2, to gather a mechanistic understanding of how A3AR agonism confers protection, we will begin our initial exploration in signaling pathways engaged at the level of the SC dorsal horn. To this end, we will examine using proteomic analysis if the beneficial effects of A3AR agonists are driven, at least in part, by inhibiting the GSK3ß & P2X7R-inflammasome pathways known to govern IL-1ß & neuroinflammation. We will also evaluate if these effects are associated with a switch from pro-inflammatory to anti-inflammatory states with increased IL-10 expression & function. We expect our results to provide a robust scientific foundation for a new translational effort in the treatment of opioid's unwanted side effects that counter-regulate opioid analgesia based upon selective "A3AR-targeted" therapies, while evaluating the potential for translational impact with A3AR agonists already in clinical trials. Selective activation of A3AR would not only transform current approaches to chronic pain, but may benefit other disorders driven by deregulation of adenosine homeostasis (i.e., drug of abuse pathologies).14 This project is a perfect fit for the CEBRA program as it meets its objectives by testing a highly novel & significant hypothesis for which there is scant information & if confirmed, would have substantial impact on current thinking in this field.