SURGERY--PROTEIN BREAKDOWN AND ENDOGENOUS OPIATES

对损伤的早期代谢反应的特点是改变 神经内分泌反应和碳水化合物异常， 氨基酸代谢 葡萄糖代谢的异常 早期并以持续高血糖为特征，其原因是 增加肝脏葡萄糖产生，降低葡萄糖利用， 肝糖原分解、糖原生成和 尿素生成 蛋白质代谢的代谢异常 后来，其特征是蛋白质分解的相对增加 而不是蛋白质合成，如果持续下去， 导致氮浪费和肌肉损失。 这种现象的确切机制 异常情况仍不清楚。 已经提出了几个假设 来解释代谢事件，有些人将这些变化归因于 相关的荷尔蒙变化，其他与增强的变化有关的变化， 生物合成和释放细胞因子、洋地黄素、白三烯等。 基于我们实验室的初步数据，本申请 提出了一个统一的假设，解释了许多激素和 伴随创伤和损伤发生的代谢事件。 我们的数据表明 损伤与血浆和CSF中的立即增加有关 一种前阿黑皮素的衍生物β-内啡肽水平。 我们也 提出的证据表明，损伤也与延迟 内源性生物碱（非肽类阿片）形成增加， 即Spector等人最近的独立工作，后来得到了 与我们实验室的斯佩克特博士合作， 这些内源性非肽生物碱的大量存在， 血浆、CSF和脑中。 有趣的是， β-内啡肽与糖代谢的变化相对应 而内源生物碱含量的变化与 氨基酸代谢 我们还提供了证据，表明许多 在创伤中观察到的分解代谢事件是由CNS激活介导的， μ受体 ICV施用吗啡或β-内啡肽或i.v. 吗啡的施用导致了显著的改变， 碳水化合物代谢与损伤后相同。 的 这一建议的一般假设是，β-内啡肽和阿片类药物 生物碱作为神经递质协同作用， 对压力刺激的内分泌、自主神经和代谢反应。 中枢神经系统β-内啡肽的升高先于吗啡的升高， 时间关系是负责的时间依赖性的变化， 碳水化合物和氨基酸代谢。 具体目标是 建议是：a）定义内生性的时间变化 β-内啡肽和非肽类阿片生物碱（吗啡， 可待因、蒂巴因）。 B）检查中央 参与葡萄糖和氨基酸代谢变化的机制 手术干预后的代谢。 我们会把这些行为 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）表征中枢阿片受体 参与调节对手术创伤的分解代谢反应。 定位外周与中枢受体的特定作用， 定义肽和非肽阿片系统之间的相互作用 来引发这些反应。

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.