ENDORPHINS AND CATECHOLAMINES IN SHOCK AND TRAUMA

本更新申请中概述的研究目的是1） 确定特异性内源性阿片肽在 出血性休克的病理生理学，2）为了进一步阐明 强啡肽和κ阿片受体系统介导的后遗症 出血性休克，3）促进改善的发展 休克的治疗方法 这个实验室的初步研究 已经证明内源性阿片类物质，包括强啡肽/k- 受体系统，可能参与心血管的调节 在休克期间发挥作用。 我们建议继续进行这些有希望的研究 使用新的可用技术来阐明 特定的阿片系统（特别是强啡肽）可介导心血管 和代谢功能障碍。 改变 在强啡肽原、前脑啡肽原和 将测量前阿黑皮素信使RNA（mRNA）（印迹 杂交）在出血前后离散脑区域中的变化 冲击. 局部脑阿片受体结合（包括kappa） 将在与以下相关的脑区域中测量 心血管调节，以检查休克对 阿片受体调节 还将采用“微穿孔”技术 检查重要的中枢心血管核团的受体变化 其可介导对休克的代偿或失代偿反应。 休克后阿片前体及受体基因表达的变化 分布将与平均动脉压的改变有关， 心输出量/每搏输出量（Cardiomax计算机），局部血流量， 脑和特定的外周血管床（放射性标记的 微球）和脑代谢（磷核磁共振 光谱-31 P NMR）。 我们还将评估是否集中 给予k-阿片受体激动剂，显微注射到离散的大脑中， 心脏调节核，加剧心血管或大脑代谢 休克时的功能障碍 最后，对两种新型药物的治疗效果进行了比较。 阿片类拮抗剂，纳美芬和nor-binaltorphimine（增加 在K位点的活性）进行评价并与纳洛酮进行比较。 这些建议的研究将加强我们对以下问题的了解： 低血压和低血流的病理生理机制 伴随休克和创伤的状态，可能导致 新的和更有效的治疗方法来治疗 失血性休克

The objectives of the studies outlined in this renewal application are 1) to establish the role of specific endogenous opioid peptides in the pathophysiology of hemorrhagic shock, 2) to further elucidate the role of the dynorphin and kappa opiate receptor system in mediating the sequelae of hemorrhagic shock, and 3) to facilitate the development of improved therapeutic approaches to shock. Preliminary studies from this laboratory have demonstrated that endogenous opioids, including the dynorphin/k- receptor system, may be involved in the regulation of cardiovascular function during shock. We propose to continue these promising studies using newly available technology to elucidate the mechanism by which specific opioid systems (particularly dynorphin) may mediate cardiovascular and metabolic dysfunction during hemorrhagic shock in the rat. Alterations in gene expression of prodynorphin, preproenkephalin and proopiomelanocortin messenger RNA (mRNA) will be measured (blot hybridization) in discrete brain regions before and after hemorrhagic shock. Changes in regional brain opiate receptor binding (including kappa isoreceptors) will be measured in brain areas associated with cardiovascular regulation in order to examine the effects of shock on opioid receptor regulation. "Micropunch" techniques will also be employed to examine receptor changes in important central cardiovascular nuclei which may mediate the compensatory or decompensatory response to shock. Post-shock changes in gene expression of opioid precursors and receptor distribution will be related to alterations in mean arterial pressure, cardiac output/stroke volume (Cardiomax computer), regional blood flow to both brain and specific peripheral vascular beds (radiolabeled microspheres) and brain metabolism (Phosphorus Nuclear Magnetic Resonance Spectroscopy -31P NMR). We will also evaluate whether centrally administered k-opioid receptor agonists, microinjected into discrete brain cardioregulatory nuclei, exacerbate cardiovascular or brain metabolic dysfunction during shock. Finally, the therapeutic efficacy of two novel opioid antagonists, nalmefene and nor-binaltorphimine (which have increased activity at k sites), will be evaluated and compared to that of naloxone. Taken together, these proposed studies will enhance our understanding of the pathophysiological mechanisms that underlie hypotension and low-flow states that accompany shock and trauma and may result in the development of new and more effective therapeutic approaches to the treatment of hemorrhagic shock.