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:
  • 金额:
    $ 54.16万
  • 依托单位:
  • 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

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.


项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Kurt F Hauser其他文献

Kurt F Hauser的其他文献

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{{ truncateString('Kurt F Hauser', 18)}}的其他基金

Chloride channel-dependent mechanisms of opiate and HIV-induced synaptodendritic injury
阿片类药物和 HIV 诱导的突触树突损伤的氯离子通道依赖性机制
  • 批准号:
    10704734
  • 财政年份:
    2022
  • 资助金额:
    $ 54.16万
  • 项目类别:
Chloride channel-dependent mechanisms of opiate and HIV-induced synaptodendritic injury
阿片类药物和 HIV 诱导的突触树突损伤的氯离子通道依赖性机制
  • 批准号:
    10548312
  • 财政年份:
    2022
  • 资助金额:
    $ 54.16万
  • 项目类别:
Innovative therapeutic approaches to address excitotoxic CNS/neuronal damage in opioid-neuroHIV comorbidity
解决阿片类药物-神经艾滋病毒合并症中的兴奋性中枢神经系统/神经元损伤的创新治疗方法
  • 批准号:
    10573827
  • 财政年份:
    2022
  • 资助金额:
    $ 54.16万
  • 项目类别:
Innovative therapeutic approaches to address excitotoxic CNS/neuronal damage in opioid-neuroHIV comorbidity
解决阿片类药物-神经艾滋病毒合并症中的兴奋性中枢神经系统/神经元损伤的创新治疗方法
  • 批准号:
    10684110
  • 财政年份:
    2022
  • 资助金额:
    $ 54.16万
  • 项目类别:
Selective vulnerability of discrete neural circuits in the striatum to HIV-opiate comorbidity
纹状体中离散神经回路对艾滋病毒-阿片类共病的选择性脆弱性
  • 批准号:
    10317037
  • 财政年份:
    2018
  • 资助金额:
    $ 54.16万
  • 项目类别:
HIV opiate interactions in white matter pathology
HIV阿片类药物在白质病理学中的相互作用
  • 批准号:
    9419501
  • 财政年份:
    2017
  • 资助金额:
    $ 54.16万
  • 项目类别:
HIV opiate interactions in white matter pathology
HIV阿片类药物在白质病理学中的相互作用
  • 批准号:
    10189540
  • 财政年份:
    2017
  • 资助金额:
    $ 54.16万
  • 项目类别:
Bivalent Ligands as Chemical Probes to Study Opioid Abuse-enhanced HIV Infection
二价配体作为化学探针研究阿片类药物滥用增强的 HIV 感染
  • 批准号:
    9924466
  • 财政年份:
    2017
  • 资助金额:
    $ 54.16万
  • 项目类别:
S1P Receptor Mechanisms in Neuropathic Pain
神经性疼痛中的 S1P 受体机制
  • 批准号:
    9775762
  • 财政年份:
    2015
  • 资助金额:
    $ 54.16万
  • 项目类别:
Chemical Probes on NeuroAIDS
神经艾滋病化学探针
  • 批准号:
    8789943
  • 财政年份:
    2014
  • 资助金额:
    $ 54.16万
  • 项目类别:

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