S1P Receptor Mechanisms in Neuropathic Pain

神经性疼痛中的 S1P 受体机制

基本信息

批准号：
9775762
负责人：
Kurt F Hauser
金额：
$ 41.13万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9775762
关键词：
Absence of pain sensation Acute Adverse effects Agonist Analgesics Astrocytes Attenuated Behavior Cells Chronic Data Depressed mood Development Disease Dose Down-Regulation Effectiveness Enterobacteria phage P1 Cre recombinase FDA approved G-Protein-Coupled Receptors GTP-Binding Proteins Gene Targeting Genetic Immune Inflammation Inflammatory Ligands Lumbar spinal cord structure Mediating Mediator of activation protein Microglia Modeling Multiple Sclerosis Mus Nerve Nervous system structure Neuraxis Neuroglia Neurons Neuropathy Nociception Nociceptors Oral Outcome Study Pain Patients Peripheral Pharmaceutical Preparations Pharmacology Pharmacotherapy Play Prodrugs Publishing Quality of life Regulation Relapse Resistance Rodent Role Site Sphingolipids Sphingosine-1-Phosphate Receptor Spinal Spinal Cord System Testing Thermal Hyperalgesias Time base cell type chronic constriction injury chronic pain desensitization edg-1 Protein experimental study genetic approach genetic manipulation glial activation inorganic phosphate mechanical allodynia midbrain central gray substance motor impairment mouse model nerve injury nestin protein neuroregulation novel novel therapeutics pain model painful neuropathy promoter protein activation public health relevance receptor receptor function response sciatic nerve sham surgery sphingosine 1-phosphate targeted treatment therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): Chronic pain diminishes the quality of life for millions of patients, but currently used classes of analgesics possess varied efficacy and are associated with a variety of untoward side effects. Thus, novel targets to treat chronic pain and development of new drugs that have better efficacy and/or fewer side effects than existing pharmacotherapies are greatly needed. A particularly promising target is the sphingosine-1-phosphate (S1P) receptor system, which mediates CNS neuromodulatory functions. FTY720-phosphate, the active metabolite of FTY720 (FTY; fingolimod), approved by the FDA for treatment of relapsing multiple sclerosis, acts as an agonist at four of the five S1P receptors (S1P1, 3, 4, 5). Interestingly, studies have demonstrated that FTY and other S1P receptor (S1PR) agonists produce antinociception in acute thermal rodent pain models and these effects are blocked by central administration of an S1P1-selective antagonist. Moreover, FTY reverses hyperalgesic states in rodent neuropathic pain models. However, it is unclear whether S1P1 or other S1PR subtypes mediate these effects and their site(s) of action. Thus, the overarching hypothesis of this application is that the S1P1 receptor represents a novel and promising target for the treatment of neuropathic pain. Here, we will test whether S1P1 receptors in the CNS mediate anti-hyperalgesic effects in a mouse neuropathic pain model, using a combination of pharmacological and gene targeting approaches. Therefore, the Specific Aims are to: 1) Determine the role of S1P1Rs in alleviation of neuropathic pain by S1PR ligands; 2) Determine the role of FTY-induced S1PR adaptation in FTY-mediated reversal of neuropathic pain; and 3) Determine the role of S1P and S1P1 receptors in spinal glia in CCI-induced neuropathic pain and its reversal by FTY. The studies proposed herein will establish whether FTY and selective S1PR ligands reverse pain-related behavior in the mouse CCI neuropathic pain model, whether S1P1 receptors in the nervous system mediate these actions and the specific cell types involved in the response. In order to be useful in treating chronic pain, the drug must retain its effectiveness during prolonged treatment. Thus, evidence supporting a role of S1P1 in specific cell types to reduce neuropathic pain without tolerance or motor impairment will provide proof of principle that S1P1 receptors are a viable target to treat neuropathic pain and possibly other chronic pain-related disorders.

描述（由适用提供）：慢性疼痛降低了数百万患者的生活质量，但目前使用的镇痛药潜在的效率各不相同，并且与多种不良副作用有关。这是比现有药物治疗效率更好和/或更少的新药物的慢性疼痛和开发的新型靶标。一个特别有希望的靶标是鞘氨醇1-磷酸（S1P）受体系统，它介导了CNS神经调节功能。 FTY720-磷酸盐是FDA的活性代谢产物（FTY; Fingerlimod），该代谢物已获得FDA治疗复发多发性硬化症的批准，在五个S1P受体中的四个（S1P1、3、3、4、5）中充当激动剂。疼痛模型和这些影响通过中央给药S1P1选择性拮抗剂阻止。此外，FTY逆转了啮齿动物神经性疼痛模型中的高温态。但是，尚不清楚S1P1或其他S1PR子类型是否介导了这些效果及其作用位置。这是该应用的总体假设是S1P1受体代表了治疗神经性疼痛的新颖和有希望的靶标。在这里，我们将使用药物和基因靶向方法的组合来测试中枢神经系统介导的小鼠神经性疼痛模型中中枢神经系统介导的抗透明效应的S1P1受体。因此，具体目的是：1）确定S1P1RS在缓解S1PR配体神经性疼痛方面的作用； 2）确定FTY诱导的S1PR适应在FTY介导的神经性疼痛反转中的作用； 3）确定S1P和S1P1受体在CCI诱导的神经性疼痛中的作用，并通过FTY逆转。本文提出的研究将确定FTY和选择性S1PR配体在小鼠CCI神经性疼痛模型中是否会反向疼痛相关的行为，神经系统中的S1P1受体是否介导了这些动作和反应中涉及的特定细胞类型。为了对治疗慢性疼痛有用，该药物必须在长期治疗期间保留其有效性。这是支持S1P1在特定细胞类型中的作用的证据，以减轻神经性疼痛而无需耐受性或运动障碍，这将提供原理证明S1P1受体是治疗神经性疼痛以及可能其他慢性疼痛疾病的可行靶标。