Peripheral Mechanisms of Opioid Analgesia

描述（由申请人提供）：本项目拨款（PPG）申请的总体目标是研究外周阿片类镇痛的机制并评估其临床疗效。该PPG应用将测试阿片类药物通过激活外周痛觉神经元上表达的阿片受体来抑制致敏痛觉受体以产生镇痛的整体假设。所有项目都将评估对缓激肽/PGE2联合作用有反应的伤害感受器。这些刺激会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，都将评估这类伤害感受器。此外，所有子项目都利用三叉神经感觉神经元，所有子项目的主要假设都在灵长类动物三叉神经培养或经历口面部疼痛的人类中进行了评估。这种统一的科学重点强调了以下子项目的相互联系和紧密编织的性质：

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.