Role of opioid-induced S1P/S1PR1 axis activation in neuroinflammatory reponses

阿片类药物诱导的 S1P/S1PR1 轴激活在神经炎症反应中的作用

• 批准号: 9751234
• 负责人: DANIELA SALVEMINI
• 金额: $ 56.57万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751234
• 关键词: Address; Alleles; Anti-inflammatory; Anxiety; Astrocytes; Attenuated; Behavior; Biochemical; Biochemical Pathway; Blocking Antibodies; Central Nervous System Diseases; Data; Dependence; Development; Dose; Evolution; FDA approved; Family; Foundations; G-Protein-Coupled Receptors; Gender; Genetic; Glutamates; Homeostasis; Hyperalgesia; IL6 gene; Image; Inflammasome; Inflammatory; Interleukin-1 beta; Interleukin-10; Intervention; Knockout Mice; Lead; Mass Spectrum Analysis; Mental Depression; Metabolism; Molecular; Molecular Target; Morphine; Motor Activity; Mus; Nervous system structure; Neuraxis; Neuropharmacology; Opioid; Oral Administration; Oxycodone; Pain; Pathway interactions; Pharmacology; Physical Dependence; Process; Production; Proteomics; Publishing; Rattus; Rewards; Rodent; Role; SPHK1 enzyme; Sedation procedure; Signal Pathway; Signal Transduction; Site; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Spinal; Spinal Cord; Spinal cord posterior horn; Structure; TNF gene; Testing; Therapeutic Intervention; Time; Ventilatory Depression; addiction; autocrine; base; cellular targeting; chronic pain; clinical translation; cytokine; genetic approach; knock-down; marenostrin; multidisciplinary; neuroinflammation; non-cancer chronic pain; novel; novel therapeutic intervention; opiate tolerance; opioid abuse; opioid use; pain relief; pain sensitivity; paracrine; receptor; research clinical testing; response; socioeconomics; sphingosine 1-phosphate; targeted agent; targeted treatment

Opioid use for chronic pain is limited by antinociceptive tolerance, opioid-induced hyperalgesia (OIH), physical dependence and addiction.1-3 The triggering mechanisms remain elusive. Our published work4,5 and preliminary data suggest for the first time that dysregulation of sphingolipid metabolism in the central nervous system (CNS) leading to exaggerated production of sphingosine 1-phosphate (S1P) and activation of an astrocyte-based S1P receptor subtype 1 (S1PR1) signaling pathway is central to these processes. Oral administration of CNS penetrant S1PR1 competitive and functional antagonists, including FTY720 (Gilenya®),6 blocked morphine and oxycodone-induced antinociceptive tolerance and OIH in rodents of both genders, as well as morphine-induced dependence and reward. FTY720 is already FDA-approved6 and therefore, rapid clinical translation of the expected finding is very feasible. We also discovered that sustained opioid-unwanted actions do not develop in conditional S1PR1-knockout mice lacking S1PR1 in spinal astrocytes and that the beneficial effects of S1PR1-targeted agents are attenuated by at least 90% in conditional S1PR1-knockdown mice of both genders, which lack one S1pr1 allele in spinal astrocytes when compared to their littermate controls. These results unravel the importance of astrocyte-based S1PR1 signaling and suggest that astrocytes are a cellular target for anti-S1PR1 activity. Increased levels of S1P in CNS were associated with increased 1) astrocyte reactivity, 2) expression of the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome (critical in IL1β formation and signaling)7 and 3) formation of inflammatory/ neuroexcitatory cytokines. Blocking S1PR1 inhibited these processes. In contrast, IL10 (an important anti- inflammatory and neuroprotective cytokine) increased significantly. Intrathecal delivery of a neutralizing anti- IL10 antibody blocked the effects of S1PR1 antagonists suggesting that their beneficial effects are driven by an endogenous IL10 pathway. A multidisciplinary plan builds on our strong preliminary data to test our hypothesis: An astrocyte-based SphK1/S1P/S1PR1 signaling pathway driven by NLRP3-induced neuroinflammation in the CNS underlies the development of morphine-induced antinociceptive tolerance/OIH and reward. Targeting S1PR1 provides a novel approach for therapeutic intervention. Three aims will test our hypothesis: 1) Establish S1PR1 as a molecular target for sustained opioid intervention, 2) Examine opioid-induced alterations of sphingolipid metabolism and SphK1/S1P/S1PR1 signaling and 3) Determine molecular and biochemical pathways engaged downstream of S1PR1 activation. Impact: Our results will unravel a previously unrecognized role for an astrocyte based SphK1/S1P/S1PR1- signaling pathway in sustained opioid use and will provide the foundation for clinical evaluation of S1PR1- targeted therapeutics as adjunct to opioids.

阿片类药物用于慢性疼痛受到抗伤害感受耐受性，阿片类药物诱导的痛觉过敏（OIH）的限制 1-3触发机制仍然难以捉摸。我们已发表的工作4,5和 初步数据首次表明中枢神经中鞘脂代谢失调 系统（CNS）导致跨越1-磷酸盐（S1P）的夸大产生和激活 基于星形胶质细胞的S1P受体亚型1（S1PR1）信号通路对于这些过程至关重要。口服 CNS渗透力S1PR1的竞争和功能拮抗剂，包括FTY720（Gilenya®），6 封闭的吗啡和羟考酮诱导的抗伤害感受耐受性和OIH在两种性别的啮齿动物中 以及吗啡引起的依赖和奖励。 FTY720已经是FDA批准的6，因此，快速 预期发现的临床翻译非常可行。我们还发现持续的阿片类药物无所 在有条件的S1PR1-敲除小鼠中，脊柱星形胶质细胞中缺乏S1PR1的行动不会发展 有条件的S1PR1-KNOCKDOWN至少90％的S1PR1靶向剂的有益作用被减弱 两种性别的小鼠，与同窝材料相比，脊柱中缺少一个S1PR1等位基因 控件。这些结果揭示了基于星形胶质细胞的S1PR1信号的重要性，并建议 星形胶质细胞是抗S1PR1活性的细胞靶标。中枢神经系统中S1P的水平升高与 增加1）星形胶质细胞反应性，2）表达点样受体家族，含有3 （NLRP3）炎性体（在IL1β形成和信号传导中至关重要）7和3）炎症/ 神经兴奋性细胞因子。阻止S1PR1抑制了这些过程。相反，IL10（一个重要的抗 鞘内递送中和 IL10抗体阻止了S1PR1拮抗剂的作用，表明它们的有益作用是由 内源性IL10途径。 多学科计划以我们强大的初步数据为基础，以检验我们的假设：基于星形胶质细胞的假设 SPHK1/S1P/S1PR1信号传导途径由NLRP3诱导的CNS中的神经炎症驱动 形态引起的抗伤害感受耐受性/OIH和奖励的发展。定位S1PR1提供 治疗干预的新方法。三个目标将检验我们的假设：1）将S1PR1确定为一个 持续阿片类干预的分子靶标2）检查阿片类药物诱导的鞘脂的改变 代谢和SPHK1/S1P/S1PR1信号传导以及3）确定参与分子和生化途径 S1PR1激活的下游。 影响：我们的结果将 揭示了基于星形胶质细胞的SPHK1/S1P/S1PR1-的先前未识别的作用 持续使用阿片类药物中的信号通路，将为S1PR1-临床评估提供基础 靶向治疗是阿片类药物的辅助治疗。