SURGERY--PROTEIN BREAKDOWN AND ENDOGENOUS OPIATES

外科手术——蛋白质分解和内源性阿片类药物

• 批准号: 2188491
• 负责人: Naji N Abumrad
• 金额: $ 29.63万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2188491
• 关键词: aminoacid metabolism; autonomic nervous system; dogs; endorphins; glucose metabolism; hormone regulation /control mechanism; injury; neuroendocrine system; opiate alkaloid; opioid receptor; pancreatic islets; postoperative state; protein degradation

The early metabolic responses to injury are characterized by alterations in the neuroendocrine responses and in abnormalities in carbohydrate and amino acid metabolism. The abnormalities in glucose metabolism occur early and are characterized by sustained hyperglycemia resulting from enhanced hepatic glucose production, decreased glucose utilization and increased rates of hepatic glycogenolysis, gluconeogenesis and ureagenesis. The metabolic abnormalities in protein metabolism occur later and are characterized by relative increases in protein breakdown over those of protein synthesis, which if they persist, will ultimately lead to nitrogen wasting and muscle loss. The exact mechanisms for such abnormalities remains obscure. Several hypotheses have been put forth to explain the metabolic events, with some attributing the changes to the associated hormonal alterations, others relating the changes to enhanced biosynthesis and release of cytokines, prostaglandins, leukotrienes, etc. Based on preliminary data from our laboratory, the present application proposes a unifying hypothesis explaining many of the hormonal and metabolic events occurring with trauma and injury. Our data indicate that injury is associated with immediate increases in plasma and CSF levels of beta-endorphin, a derivative of proopiomelanocortin. We also presented evidence to suggest that injury is also associated with delayed increases in the formation of endogenous alkaloids (non-peptide opiates), namely recent independent work by Spector et al. nd later confirmed by collaborative work with Dr. Spector in our laboratory identified the presence of these endogenous non-peptide alkaloids in high quantities in plasma, CSF and in brain. Interestingly, the temporal changes in the beta-endorphin corresponded with the changes in carbohydrate metabolism while the changes in endogenous alkaloids corresponded with those of amino acid metabolism. We also presented evidence showing that many of the catabolic events seen with trauma are mediated by CNS activation of mu-receptors. ICV administration of morphine or beta-endorphin or i.v. administration of morphine resulted in significant alterations in carbohydrate metabolism identical to those seen after injury. The General Hypothesis of this proposal is that beta-endorphin and the opioid alkaloids act synergistically as neurotransmitters integrating most of the endocrine, autonomic and metabolic responses to stressful stimuli. The rises in CNS beta-endorphin precede those of morphine, and that this temporal relationship is responsible for the time-dependent changes in carbohydrate and in amino acid metabolism. The Specific Aims of this proposal are: a) to define the temporal changes in the endogenous responses of beta-endorphin, and non-peptide opiate alkaloids (morphine, codeine, thebaine) during the stress of surgery. b) Examine the central mechanisms involved in the metabolic changes in glucose and amino acid metabolism following surgical intervention. We will isolate the actions of the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and the endocrine pancreas to determine their relative contributions to the observed changes. c) Characterize the central opiate receptors involved in modulating the catabolic response to operative trauma. Localize the specific actions of peripheral versus central receptors and define the interactions between peptide and non-peptide opiate systems in eliciting those responses.

对损伤的早期代谢反应以改变为特征。 在神经内分泌反应和碳水化合物和 氨基酸代谢。葡萄糖代谢会出现异常 早期并以以下原因引起的持续性高血糖为特征 增加肝脏葡萄糖的产生，降低葡萄糖的利用 肝脏糖原分解、糖异生和 尿失禁。蛋白质代谢出现代谢异常 较晚，以蛋白质分解相对增加为特征 而不是蛋白质合成，如果它们持续下去，最终 会导致氮的浪费和肌肉的丧失。这种情况的确切机制是 异常情况仍不清楚。已经提出了几个假说 来解释代谢事件，一些人将这些变化归因于 相关的激素变化，其他人将这些变化与增强 细胞因子、前列腺素、白三烯等的生物合成和释放。 基于我们实验室的初步数据，本申请 提出了一个统一的假说，解释了许多荷尔蒙和 伴随着创伤和损伤而发生的代谢事件。我们的数据显示 这种损伤与血浆和脑脊液的即刻增加有关。 原阿片黑素皮质素的衍生物--β-内啡肽水平。我们也 提出的证据表明，伤害也与延迟有关 增加内源性生物碱(非肽阿片类)的形成， 即Spector等人最近的独立工作。随后由以下人员确认 与斯佩克特博士在我们实验室的合作发现了 这些内源性非肽生物碱在中国的含量很高 血浆、脑脊液和脑内。有趣的是，时间上的变化 β-内啡肽与碳水化合物代谢的变化相对应 而内源生物碱的变化与黄瓜的变化一致。 氨基酸代谢。我们还提供了证据表明，许多人 创伤所见的分解代谢事件是由中枢神经系统激活 MU受体。脑室注射吗啡或β-内啡肽或静脉注射。 注射吗啡后，脑组织中 碳水化合物代谢与受伤后相同。这个 这一提议的一般假设是β-内啡肽和阿片类药物 生物碱作为神经递质协同作用，整合了大多数 内分泌、自主神经和代谢对应激刺激的反应。 中枢神经系统β-内啡肽的升高先于吗啡的升高，而这 时间关系是导致时间依赖的变化的原因 碳水化合物和氨基酸代谢中。这样做的具体目的是 建议是：a)定义内生的时间变化 β-内啡肽和非肽阿片生物碱(吗啡、 可待因、丁巴因)。B)检查中央 葡萄糖和氨基酸代谢变化的机制 手术干预后的新陈代谢。我们将隔离这些行动 下丘脑-垂体-肾上腺轴，自主神经系统， 和内分泌胰腺，以确定它们对 观察到的变化。C)确定中枢阿片受体的特征 参与调节对手术创伤的分解代谢反应。 定位外周受体对中枢受体的特定作用 定义多肽和非多肽阿片系统之间的相互作用 在引发这些反应方面。