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（适用提供）：阿片类药物用于长期治疗慢性疼痛的限制受到相对较差的效率和自适应中枢神经系统变化的出现，从而导致镇痛耐受性，增加疼痛，增加疼痛（阿片类药物诱导的超敏性，OIH）和身体依赖性，以弥补健康的劳动责任。通过A3 GPCR亚型，腺苷接收器（A3AR）及其控制腺苷激酶（ADK）通过镇痛耐受性，OIH和依赖性控制腺苷神经调节。该提案强调了一项多学科研究计划，旨在探索ADK-TO-A3AR轴和A3AR激动剂适用性的贡献，同时研究其基本的保护机制和中枢神经系统中的作用部位。值得注意的是，A3AR激动剂，例如IB-MECA及其2-氯类似物（Cl-ib-Meca），已成为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AIM 1中，我们将在AIM 1中进行良好的安全性。和遗传/蛋白质组学分析）。同时，SC＆CSF中的嘌呤核侧浓度（来自腰椎穿刺）将通过靶向的代谢方法测量。我们将（1）通过剂量响应曲线和时间过程进行A3AR激动剂的药物概况，以及性别对A3AR效应的影响及（2）研究SC作为行动部位的贡献。作为推论，我们将通过测试Oxycodon和A3AR激动剂来探讨发现的临床概括，并研究the腹腹膜髓质（RVM）的贡献，作为附加的作用部位。在AIM 2中，为了收集对A3AR激动剂保护的机械理解，我们将开始在SC背角级别接合的信号通路中初步探索。为此，我们将使用蛋白质组学分析检查A3AR激动剂的有益作用至少部分通过抑制GSK3ß和P2X7R-炎症途径驱动，以控制IL-1ß和神经炎症。我们还将评估这些效果是否与从促炎性态转变为具有IL-10表达和功能增加的抗炎状态的转换有关。我们希望我们的结果为新的翻译努力提供了强大的科学基础，以治疗阿片类药物的不需要副作用，该副作用基于选择性“ A3AR靶向”疗法来对抗阿片类镇痛，同时评估已经在临床试验中已经对A3AR激动剂的翻译影响潜力。 A3AR的选择性激活不仅会使当前的方法转化为慢性疼痛，而且可能受益于腺苷稳态放松造成的其他疾病（即滥用病理学的药物）。14该项目非常适合CEBRA计划，因为它通过测试了一个高度新颖的假设，即确认了这一验证，并且在这种情况下对此进行了验证，并实现了这种验证，并实现了这一验证，并实现了这一验证，并实现了这一验证，并实现了验证，并在此实现了验证，并且会遇到任何验证，并在此实现了验证。