ENDORPHINS IN SHOCK AND TRAUMA

本续期申请书中概述的研究目标为1) 目的：确定特定的内源性阿片肽在脑出血中的作用。 失血性休克的病理生理学，2)进一步阐明 强啡肽和kappa阿片受体系统在介导糖尿病后遗症中的作用 失血性休克，以及3)促进发展的改善 治疗休克的方法。来自该实验室的初步研究 已经证明内源性阿片类药物，包括强啡肽/k- 受体系统，可能参与心血管的调节 在电击时起作用。我们建议继续这些有希望的研究 利用最新可用的技术来阐明 特定的阿片系统(尤其是强啡肽)可能调节心血管 失血性休克大鼠的代谢功能障碍。改建 前强啡肽原、前脑啡肽原和前脑啡肽原基因表达 测定原阿片黑素皮质素信使核糖核糖核酸(MRNA) 杂交)在出血前和出血后的离散脑区 令人震惊。局部脑阿片受体结合的变化(包括kappa 等受体)将在脑部相关区域进行测量 心血管调节，以检查休克对 阿片受体调节。还将采用“微冲压”技术。 检测重要的心血管中枢核团的受体变化 它可能调节对休克的代偿性或失代偿性反应。 休克后阿片前体及其受体基因表达的变化 分布将与平均动脉压的变化有关， 心输出量/每搏输出量(心脏最大计算机)，区域血流量 脑部和特定的外周血管床(放射性标记 微球)和脑代谢(磷核磁共振 光谱学-31P核磁共振)。我们还将评估中央是否 给予K-阿片受体激动剂，离散脑内显微注射 心脏调节核团，加剧心血管或大脑代谢 休克时的功能障碍。最后，比较两种新药的治疗效果。 阿片类拮抗剂，纳美芬和去甲双酚亚胺(增加了 K个位点的活性)，将进行评估并与纳洛酮进行比较。 综上所述，这些建议的研究将加深我们对 低血压和低流量的病理生理机制 伴随着休克和创伤的状态，可能导致 新的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.