Preserving opioid analgesia using a novel adenosinergic approach

使用新型腺苷能方法保持阿片类镇痛作用

• 批准号: 9095273
• 负责人: DANIELA SALVEMINI
• 金额: $ 18.75万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095273
• 关键词: Absence of pain sensation; Adenosine; Adenosine A3 Receptor; Adenosine Kinase; Adult; Adverse effects; Agonist; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Area; Astrocytes; Attenuated; Brain; Chronic; Clinical; Clinical Trials; Communities; Data; Dependence; Development; Disease; Dose; Drug Kinetics; Excision; Feedback; Foundations; Functional disorder; G-Protein-Coupled Receptors; Gender; Genetic; Grant; Health; Health Care Costs; Homeostasis; Hypersensitivity; Immune; Immunofluorescence Immunologic; Inflammatory; Injection of therapeutic agent; Interdisciplinary Study; Interleukin-1; Interleukin-1 beta; Interleukin-10; Intrathecal Injections; Link; Measures; Metabolic; Microglia; Morphine; Naloxone; Neuraxis; Neuroglia; Neurons; Nucleoside Transporter; Opioid; Opioid Analgesics; Oral; Oxycodone; Pain; Pathology; Pathway interactions; Pharmaceutical Preparations; Phase; Physical Dependence; Process; Proteomics; Public Health; Purine Nucleosides; Purinergic P1 Receptors; Rattus; Receptor Signaling; Reporting; Rodent; Safety; Side; Signal Pathway; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Puncture; Spinal cord posterior horn; Synaptic Transmission; Testing; Therapeutic; Thinking; Time; Up-Regulation; Withdrawal; addiction; analog; attenuation; base; chronic pain; cytokine; drug of abuse; extracellular; glial activation; meetings; neuroinflammation; neuroregulation; non-cancer pain; novel; opiate tolerance; opioid use; painful neuropathy; prevent; programs; response; targeted treatment

 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.

 描述（由申请人提供）：阿片类药物长期治疗慢性疼痛的使用受到相对较差的疗效和适应性中枢神经系统变化的出现的限制，这些变化导致镇痛耐受、增加疼痛（阿片类药物引起的超敏反应，OIH）和身体依赖性抵消镇痛作用，造成健康负担并造成社区滥用责任。1-9 我们现在首次暗示阿片类药物通过 A3 引起腺苷神经调节功能障碍GPCR 亚型、腺苷受体 (A3AR) 及其在镇痛耐受、OIH 和依赖性方面受腺苷激酶 (AdK) 的控制本提案强调了一项多学科研究计划，旨在探索 AdK 至 A3AR 轴的贡献和广泛性。 A3AR 激动剂的适用性，同时研究其潜在的保护机制和中枢神经系统的作用位点值得注意的是，A3AR 激动剂，例如 IB-MECA 和其 2-氯类似物 (Cl-IB-MECA) 作为新型抗炎和抗癌药物已进入 II/III 期临床试验，具有良好的安全性。10-13 在目标 1 中，我们将研究时间和细胞表达SC 神经胶质细胞和神经元中的 AdK（及其酶活性）和 A3AR（免疫荧光和遗传/蛋白质组学分析）同时，SC 和 CSF 中的嘌呤核苷浓度（来自腰椎穿刺）。我们将通过有针对性的代谢方法来测量（1）通过剂量反应曲线和时程研究以及性别对 A3AR 效应的影响来表征 A3AR 激动剂的逻辑药理学特征；（2）检查 SC 的贡献作为一个推论，我们将通过测试羟考酮和 A3AR 激动剂来探索结果的临床概括，并检查头端腹内侧延髓 (RVM) 作为作用位点的附加作用。在目标 2 中，为了收集 A3AR 激动如何提供保护的机制，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是否有益。 A3AR 激动剂的作用至少部分是通过抑制已知控制 IL-1ß 和神经炎症的 GSK3ß 和 P2X7R 炎症体途径来驱动的。评估这些效应是否与 IL-10 表达和功能增加从促炎状态转变为抗炎状态有关。我们希望我们的结果能够为治疗阿片类药物不良副作用的新转化努力提供坚实的科学基础。基于选择性“A3AR 靶向”疗法来反调节阿片类镇痛，同时评估已在临床试验中的 A3AR 激动剂的转化影响潜力，A3AR 的选择性激活不仅会改变目前治疗慢性疼痛的方法，而且可能有益于其他治疗方法。由腺苷稳态失调（即滥用药物病理学）引起的疾病。 14 该项目非常适合 CEBRA 计划，因为它通过测试一个高度新颖且重要的假设来实现其目标，但该假设的信息很少，如果得到证实，将对当前该领域的思想产生重大影响。