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.
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