权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9750825
负责人：
Kurt F Hauser
金额：
$ 54.16万
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 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750825
关键词：
Absence of pain sensation Acute 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 side effect 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.