SURGERY--PROTEIN BREAKDOWN AND ENDOGENOUS OPIATES

损伤的早期代谢反应以改变为特征

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.