Peripheral Mechanisms of Opioid Analgesia

阿片类镇痛的外周机制

• 批准号: 7228957
• 负责人: Kenneth M Hargreaves
• 金额: $ 69.17万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228957
• 关键词: Peripheral; Mechanisms; Opioid; Analgesia

DESCRIPTION (provided by applicant): The overall objective of this program project grant (PPG) application is to investigate the mechanisms and evaluate the clinical efficacy of peripheral opioid analgesia. This PPG application will test the overall hypothesis that opioids inhibit sensitized nociceptors via activation of opioid receptors expressed on peripheral nociceptive neurons to produce analgesia. All projects will evaluate nociceptors that respond to a combination of bradykinin/PGE2. These stimuli activate nociceptors involved with many pain conditions. All of the sub-projects, from cell culture to clinical trials, will evaluate this same class of nociceptors. In addition, all sub-projects utilize trigeminal sensory neurons with major hypotheses from all sub-projects evaluated in either primate trigeminal neuron cultures or in humans experiencing orofacial pain. This unifying scientific focus emphasizes the interrelatedness and tightly woven nature of the following sub-projects: Sub-Project 0001 (PI: W. Clarke): Determine signal transduction pathways in sensory neurons that: 1) induce functional competence in pre-existing "silent" mu- (MOR), delta- (DOR) and kappa- (KOR) opioid receptors on sensory neurons; 2) mediate opioid ligand-dependent signaling by activation of MOR, DOR or KOR. Sub-Project 0002 (PI: S. Milam): Determine the effects of integrin-neuronal interactions on the expression, trafficking and function of the MOR, DOR and KOR on cultured sensory neurons. Sub-Project 0003 (PI: K. Hargreaves): Determine the effects of peripheral MOR, DOR and KOR selective agonists on nociceptor activation in biopsies taken from normal healthy patients versus patients with inflammatory pain, and characterize the peripheral analgesic effects of mu versus kappa opioid agonists. Collectively, these studies provide a comprehensive evaluation of the hypotheses that opioids inhibit sensitized nociceptors via activation of opioid receptors expressed on peripheral nociceptive neurons to produce analgesia. In addition, these sub-projects will characterize mechanisms regulating opioid receptor function in trigeminal sensory neurons.

描述（由申请人提供）：本项目资助（PPG）申请的总体目标是研究外周阿片类镇痛的机制并评价其临床疗效。该PPG应用将检验阿片类药物通过激活外周伤害感受神经元上表达的阿片类受体抑制致敏伤害感受器以产生镇痛的总体假设。所有项目将评估对缓激肽/PGE 2组合作出反应的伤害感受器。这些刺激激活与许多疼痛状况有关的伤害感受器。所有的子项目，从细胞培养到临床试验，都将评估同一类伤害感受器。此外，所有的子项目利用三叉神经感觉神经元与主要假设，从所有的子项目评估灵长类动物三叉神经元文化或人类经历orofacial疼痛。这一统一的科学重点强调了以下子项目的相互关联和紧密交织的性质： 子项目0001（PI：W. Clarke）：确定感觉神经元中的信号转导途径，其：1）诱导感觉神经元上预先存在的“沉默”μ-（莫尔）、δ-（DOR）和κ-（KOR）阿片受体的功能能力; 2）通过激活莫尔、DOR或KOR介导阿片配体依赖性信号传导。 子项目0002（PI：S. Milam）：确定整联蛋白-神经元相互作用对培养的感觉神经元上的莫尔、DOR和KOR的表达、运输和功能的影响。 子项目0003（PI：K.哈格里夫斯）：确定外周莫尔、DOR和KOR选择性激动剂对正常健康患者与炎性疼痛患者活检组织中伤害感受器激活的影响，并表征μ与κ阿片激动剂的外周镇痛作用。 总的来说，这些研究提供了一个全面的评估的假设，阿片类药物抑制敏感的伤害感受器通过激活阿片受体表达的外周伤害感受神经元产生镇痛。此外，这些子项目将表征调节三叉神经感觉神经元中阿片受体功能的机制。