Preserving opioid analgesia using a novel adenosinergic approach

 描述（申请人提供）：阿片类药物用于慢性疼痛的长期治疗受到疗效相对较差的限制&适应性中枢神经系统变化的出现导致镇痛耐受，增加疼痛，（阿片类药物诱导的超敏反应，OIH）和抵消镇痛的身体依赖，造成健康负担并产生社区滥用责任。1 -9我们现在第一次通过A3 GPCR亚型暗示阿片类药物诱导的腺苷神经调节功能障碍，腺苷受体（A3 AR）及其受腺苷激酶（AdK）的调控在镇痛耐受、OIH和依赖中的作用。该提案强调了一项多学科研究计划，旨在探索AdK-to-A3 AR轴的贡献和A3 AR激动剂适用性的广度，同时研究其潜在的保护机制和CNS中的作用位点。值得注意的是，A3 AR激动剂，如IB-MECA及其2-氯类似物（Cl-IB-MECA），已进入II/III期临床试验，作为具有良好安全性的新型抗炎和抗癌药物。10 -13在目标1中，我们将研究AdK（及其酶活性）和A3 AR在SC神经胶质细胞和神经元中的时间和细胞表达（免疫荧光和遗传/蛋白质组学分析）。同时，将通过靶向代谢方法测量SC和CSF（来自腰椎穿刺）中的嘌呤核苷浓度。我们将（1）通过剂量-反应曲线和时间过程研究以及性别对A3 AR效应的影响来表征A3 AR激动剂的药理学特征;（2）检查SC作为作用部位的贡献。作为一个必然的结果，我们将探索临床推广的结果，通过测试oxycodon和A3 AR激动剂和检查的头端腹内侧延髓（RVM）的贡献，作为一个额外的网站的行动。在目标2中，为了从机制上理解A3 AR激动如何赋予保护作用，我们将开始对SC背角水平的信号通路进行初步探索。为此，我们将使用蛋白质组学分析来检查A3 AR激动剂的有益作用是否至少部分地通过抑制已知控制IL-1 β和神经炎症的GSK 3 β和P2 X7 R-炎性体途径来驱动。我们还将评估这些作用是否与从促炎状态到抗炎状态的转换以及IL-10表达和功能的增加有关。我们希望我们的研究结果为治疗阿片类药物的不良副作用提供一个强大的科学基础，这些副作用基于选择性的“A3 AR靶向”疗法来反调节阿片类药物镇痛，同时评估A3 AR激动剂的潜在翻译影响已经在临床试验中。A3 AR的选择性激活不仅会改变目前治疗慢性疼痛的方法，而且可能有益于由腺苷稳态失调驱动的其他疾病（即，14该项目非常适合CEBRA计划，因为它通过测试一个非常新颖和重要的假设来实现其目标，该假设缺乏信息，如果得到证实，将对该领域的当前思想产生重大影响。

 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.