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

基本信息

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
项目类别：
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

项目摘要

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.

阿片类药物用于治疗慢性疼痛受到抗药耐受、阿片类药物诱发的痛觉过敏 (OIH)、身体依赖和成瘾。1-3 我们发表的工作4,5 和触发机制仍然难以捉摸。初步数据首次表明中枢神经系统鞘脂代谢失调系统（CNS）导致1-磷酸鞘氨醇（S1P）的过量产生并激活基于星形胶质细胞的 S1P 受体亚型 1 (S1PR1) 信号通路是这些过程的核心。给予中枢神经系统渗透性 S1PR1 竞争性和功能性拮抗剂，包括 FTY720 (Gilenya®)，6 阻断吗啡和羟考酮诱导的两种性别啮齿类动物的抗伤害耐受和 OIH，以及吗啡引起的依赖性和奖励 FTY720 已获得 FDA 批准6，因此进展迅速。预期结果的临床转化是非常可行的，我们还发现持续的阿片类药物是不需要的。在脊髓星形胶质细胞中缺乏 S1PR1 的条件性 S1PR1 敲除小鼠中，不会产生作用，并且在条件性 S1PR1 敲低中，S1PR1 靶向药物的有益效果至少减弱 90% 与同窝小鼠相比，脊髓星形胶质细胞中缺少一个 S1pr1 等位基因的雌雄小鼠这些结果揭示了基于星形胶质细胞的 S1PR1 信号传导的重要性，并表明星形胶质细胞是抗 S1PR1 活性的细胞靶标，中枢神经系统中 S1P 水平的升高与此相关。增加 1) 星形胶质细胞反应性，2) Nod 样受体家族表达，pyrin 结构域包含 3 (NLRP3) 炎症小体（对于 IL1β 形成和信号转导至关重要）7 和 3) 炎症/的形成相比之下，IL10（一种重要的抗-神经兴奋性细胞因子）会抑制这些过程。鞘内注射中和性抗-炎症和神经保护细胞因子显着增加。 IL10 抗体阻断 S1PR1 拮抗剂的作用，表明它们的有益作用是由内源性 IL10 途径。多学科计划建立在我们强大的初步数据的基础上来检验我们的假设：基于星形胶质细胞的由 NLRP3 诱导的 CNS 神经炎症驱动的 SphK1/S1P/S1PR1 信号通路是吗啡诱导的抗伤害耐受/OIH 和奖赏的发展提供了一种机制。治疗干预的新方法将检验我们的假设的三个目标：1）将 S1PR1 建立为持续阿片类药物干预的分子靶标，2) 检查阿片类药物诱导的鞘脂变化代谢和 SphK1/S1P/S1PR1 信号传导以及 3) 确定参与的分子和生化途径 S1PR1 激活的下游。影响：我们的结果将揭示基于星形胶质细胞的 SphK1/S1P/S1PR1 的先前未被认识的作用- 持续阿片类药物使用中的信号通路，将为 S1PR1- 的临床评估提供基础作为阿片类药物辅助药物的靶向治疗。