ENDORPHINS AND CATECHOLAMINES IN SHOCK AND TRAUMA

所概述的研究的目标是确定 特异性内源性阿片肽在慢性阻塞性肺疾病病理生理中的作用 失血性休克及促进发展的改进 休克和创伤的治疗方法。初步研究 已经证明了内源性阿片类药物， 包括强啡肽/kappa受体系统，可能参与其中 在休克时对心血管功能的调节。我们 建议使用最新可用的技术来阐明 特定阿片系统的调节机制 失血性休克时的心血管功能障碍。在 拟议的研究、特定阿片肽的作用(特别是 强啡肽)和阿片受体 大鼠急性失血性休克的病理生理研究。 阿片肽和儿茶酚胺的血浆浓度将 在休克诱导前后进行测定。变化 脑内阿片受体结合部位与脑内阿片类药物 免疫反应性将在相关的特定区域进行测量 来自对照和受伤动物的心血管调节 为研究休克对局部多肽的影响 药物浓度和阿片受体分布。“微型打孔机” 还将使用技术来检查阿片类药物 重要中枢神经系统的免疫反应性和受体变化 心血管核团可能介导代偿性或 对电击的失代偿反应。休克后血浆的变化 阿片浓度，中枢神经系统阿片类药物 免疫反应性和受体分布将与 平均动脉压、心输出量/卒中的变化 特定外周血管的血流量和区域血流量 床。为了进一步确定强啡肽和/或kappa是否- 阿片受体导致休克后遗症，我们会 评估中枢应用kappa-阿片受体 激动剂加剧了对休克的生理反应。最后， 两种新型阿片类拮抗剂的疗效观察 纳美芬和WIN44,441-3(它们在 Kappa站点)将进行评估并与纳洛酮进行比较 失血性休克。综上所述，这些拟议研究将 加深对其病理生理机制的认识 这是伴随低血压和低流量状态的基础 休克和创伤，并可能导致新的和 更有效的治疗方法 失血性休克。

The objectives of the studies outlined are to establish the role of specific endogenous opioid peptides in the pathophysiology of hemorrhagic shock and to facilitate the development of improved therapeutic approaches to shock and trauma. Preliminary studies from this laboratory have demonstrated that endogenous opioids, including the dynorphin/kappa-receptor system, may be involved in the regulation of cardiovascular function during shock. We propose to use newly available technology to elucidate the mechanism by which specific opioid systems mediate cardiovascular dysfunction during hemorrhagic shock. In the proposed studies, the role of specific opioid peptides (particularly dynorphin) and opioid receptors will be examined with regard to the pathophysiology of acute hemorrhagic shock in the rat. Plasma concentrations of opioid peptides and catecholamines will be determined before and after the induction of shock. Changes in brain opiate receptor binding sites and brain opiate immunoreactivity will be measured in specific regions associated with cardiovascular regulation from control and injured animals in order to examine the effects of shock on regional peptide concentrations and opioid receptor distribution. "Micropunch" techniques will also be employed to examine opioid immunoreactivity and receptor changes in important central cardiovascular nuclei which may mediate the compensatory or decompensatory response to shock. Post-shock changes in plasma opioid concentration, central nervous system opiate immunoreactivity and receptor distribution will be related to alterations in mean arterial pressure, cardiac output/stroke volume and regional blood flow to specific peripheral vascular beds. To further determine whether dynorphin and/or the kappa- opiate receptor contribute to the sequelae of shock, we will evaluate whether centrally administered kappa-opioid receptor agonists exacerbate the physiological response to shock. Finally, the therapeutic efficacy of two novel opioid antagonists nalmefine and WIN44,441-3 (which have increased activity at kappa sites) will be evaluated and compared to that of naloxone in hemorrhagic shock. 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.