Peripheral Mechanisms of Opioid Analgesia

描述(申请人提供)：本计划项目资助(PPG)申请的总体目标是研究外周阿片类药物镇痛的机制和评估临床疗效。这一PPG应用将检验阿片类药物通过激活外周伤害性神经元上表达的阿片受体来抑制敏感型伤害性感受器产生镇痛的总体假设。所有项目都将评估对缓激肽/PGE2组合有反应的伤害性感受器。这些刺激激活了与许多疼痛情况有关的伤害性感受器。所有的子项目，从细胞培养到临床试验，都将评估这一类伤害性感受器。此外，所有子项目都使用三叉神经感觉神经元，主要假设来自所有子项目，在灵长类三叉神经细胞培养中或在经历口面部疼痛的人类中进行评估。这一统一的科学重点强调以下分项目的相互关联性和紧密交织性质： 子项目0001(PI：W.Clarke)：确定感觉神经元中的信号转导通路：1)在感觉神经元上诱导预先存在的“沉默的”阿片受体的功能能力；2)通过激活MOR、DOR或KOR来介导阿片配体依赖的信号传递。 子项目0002(PI：S.Milam)：确定整合素-神经元相互作用对培养的感觉神经元上MOR、DOR和KOR的表达、运输和功能的影响。 子项目0003(PI：K.Hargreaves)：确定外周MOR、DOR和KOR选择性激动剂对正常健康患者和炎性疼痛患者活检组织中伤害性感受器激活的影响，并表征MU和Kappa阿片类激动剂的外周止痛效果。 总而言之，这些研究对阿片类药物通过激活外周伤害性神经元上表达的阿片受体而抑制敏感型伤害性感受器产生镇痛的假说进行了全面的评估。此外，这些子项目将描述三叉神经感觉神经元中阿片受体功能的调节机制。

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.