Mechanisms of analgesia by peripheral viral vector insertion of opioid receptors.

阿片受体外周病毒载体插入的镇痛机制。

基本信息

  • 批准号:
    8780191
  • 负责人:
  • 金额:
    $ 3.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-06 至 2015-04-15
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Neuropathic pain is a highly prevalent and severely distressing condition thought to result from spontaneous activity and sensitization of peripheral nerve fibers, especially nociceptors that signal pain from the periphery. Opioid therapy has been shown to be effective in attenuating neuropathic pain clinically; however their central nervous system effects including sedation, impaired cognitive function and abuse potential limit their usefulness in patient care. Input from sensitized nerve fibers can result in an altered spinal cord processing of thermal and mechanical stimuli (central sensitization). Analgesia from opioid receptor activation on nerve fibers causes a decrease of neuropeptide and neurotransmitter release and inhibition of pain signal propagation to the brain. Previous studies have shown that gene therapy treatment using recombinant herpes simplex-1 (HSV-1) viral vector expressing the mu-opioid receptor (MOR) increases MOR expression on peripheral nerve fibers and enhances heat pain analgesia after opioid treatment in rodents. It is unknown if the analgesia from opioid receptor viral vector therapy is mediated at the peripheral or central terminals of nociceptors. The proposed experiments explore the mechanisms of pain reduction through viral vector therapy. The specific aim outlined in this proposal is: 1) To determine if over-expression of MORs in peripheral nerve fibers enhances opioid sensitivity and decreases primary afferent neuron responses to noxious stimulation post morphine application in neuropathic animals. In these experiments we will inoculate the hindpaw of chronic constriction injury (CCI) mice with an HSV-1 viral vector containing either the construct for either the MOR (SGMOR), the μ-opioid receptor in the anti-sense direction (SGAMOR) or the β-galactosidase gene (SGZ) as a control. We will implement single fiber skin nerve recordings to investigate the peripheral mechanisms of opiate analgesia after gene therapy. The hypotheses of the proposal are that morphine will 1) greatly decrease responses of noxious stimulation in peripheral nociceptors and 2) reduce spontaneous activity from nociceptors in neuropathic (CCI) animals after MOR viral vector therapy. Opioid drugs that target peripheral nociceptors without affecting the central nervous system may be able to reduce pain and prevent adverse side effects seen with many current opioid therapies. The future long-term goal of this project is to use MOR gene therapy for chronic and neuropathic pain conditions in humans.
描述(由申请人提供):神经性疼痛是一种非常普遍且严重令人痛苦的病症,被认为是由周围神经纤维(尤其是从周围发出疼痛信号的伤害感受器)的自发活动和敏化引起的。临床显示阿片类药物治疗可有效减轻神经性疼痛;然而,它们对中枢神经系统的影响,包括镇静、认知功能受损和滥用潜力,限制了它们在患者护理中的用途。来自敏化神经纤维的输入可能会导致脊髓对热和机械刺激的处理发生改变(中枢敏化)。神经纤维上的阿片受体激活产生的镇痛作用会导致神经肽和神经递质释放减少,并抑制疼痛信号传播到大脑。先前的研究表明,使用表达μ阿片受体(MOR)的重组单纯疱疹-1(HSV-1)病毒载体进行基因治疗可增加周围神经纤维上MOR的表达,并增强啮齿类动物阿片类药物治疗后的热痛镇痛效果。目前尚不清楚阿片受体病毒载体疗法的镇痛作用是否是在伤害感受器的外周或中央末端介导的。拟议的实验探讨了通过病毒载体疗法减轻疼痛的机制。该提案概述的具体目标是: 1) 确定神经病动物外周神经纤维中 MOR 的过度表达是否会增强阿片类药物敏感性并降低初级传入神经元对吗啡应用后有害刺激的反应。在这些实验中,我们将用含有 MOR (SGMOR)、反义方向 μ-阿片受体 (SGAMOR) 或 β-半乳糖苷酶基因 (SGZ) 构建体的 HSV-1 病毒载体接种慢性缩窄性损伤 (CCI) 小鼠的后爪作为对照。我们将实施单纤维皮肤神经记录来研究基因治疗后阿片镇痛的外周机制。该提案的假设是,吗啡将 1) 大大降低外周伤害感受器对伤害性刺激的反应,2) 减少 MOR 病毒载体治疗后神经病 (CCI) 动物伤害感受器的自发活动。以外周伤害感受器为目标而不影响中枢神经系统的阿片类药物可能能够减轻疼痛并防止当前许多阿片类药物治疗中出现的不良副作用。该项目未来的长期目标是利用 MOR 基因疗法治疗人类慢性和神经性疼痛。

项目成果

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Amanda Helen Klein其他文献

Amanda Helen Klein的其他文献

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{{ truncateString('Amanda Helen Klein', 18)}}的其他基金

KATP Channels as Downstream targets of adenylyl cyclases during opioid tolerance and withdrawal
KATP 通道作为阿片类药物耐受和戒断期间腺苷酸环化酶的下游靶标
  • 批准号:
    10451672
  • 财政年份:
    2021
  • 资助金额:
    $ 3.82万
  • 项目类别:
KATP Channels as Downstream targets of adenylyl cyclases during opioid tolerance and withdrawal
KATP 通道作为阿片类药物耐受和戒断期间腺苷酸环化酶的下游靶标
  • 批准号:
    10317189
  • 财政年份:
    2021
  • 资助金额:
    $ 3.82万
  • 项目类别:
KATP Channels as Downstream targets of adenylyl cyclases during opioid tolerance and withdrawal
KATP 通道作为阿片类药物耐受和戒断期间腺苷酸环化酶的下游靶标
  • 批准号:
    10618258
  • 财政年份:
    2021
  • 资助金额:
    $ 3.82万
  • 项目类别:
Altering potassium channel activity to investigate morphine tolerance and opiate induced hypersensitivity
改变钾通道活性以研究吗啡耐受性和阿片类药物引起的超敏反应
  • 批准号:
    10088427
  • 财政年份:
    2018
  • 资助金额:
    $ 3.82万
  • 项目类别:
Altering potassium channel activity to investigate morphine tolerance and opiate induced hypersensitivity
改变钾通道活性以研究吗啡耐受性和阿片类药物引起的超敏反应
  • 批准号:
    10349435
  • 财政年份:
    2018
  • 资助金额:
    $ 3.82万
  • 项目类别:

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2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
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    Discovery Grants Program - Individual
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