The objectives of the studies outlined in this renewal application are 1) to establish the role of specific endogenous opioid peptides in the pathophysiology of hemorrhagic shock, 2) to further elucidate the role of the dynorphin and kappa opiate receptor system in mediating the sequelae of hemorrhagic shock, and 3) to facilitate the development of improved therapeutic approaches to shock. Preliminary studies from this laboratory have demonstrated that endogenous opioids, including the dynorphin/k- receptor system, may be involved in the regulation of cardiovascular function during shock. We propose to continue these promising studies using newly available technology to elucidate the mechanism by which specific opioid systems (particularly dynorphin) may mediate cardiovascular and metabolic dysfunction during hemorrhagic shock in the rat. Alterations in gene expression of prodynorphin, preproenkephalin and proopiomelanocortin messenger RNA (mRNA) will be measured (blot hybridization) in discrete brain regions before and after hemorrhagic shock. Changes in regional brain opiate receptor binding (including kappa isoreceptors) will be measured in brain areas associated with cardiovascular regulation in order to examine the effects of shock on opioid receptor regulation. """"""""Micropunch"""""""" techniques will also be employed to examine receptor changes in important central cardiovascular nuclei which may mediate the compensatory or decompensatory response to shock. Post-shock changes in gene expression of opioid precursors and receptor distribution will be related to alterations in mean arterial pressure, cardiac output/stroke volume (Cardiomax computer), regional blood flow to both brain and specific peripheral vascular beds (radiolabeled microspheres) and brain metabolism (Phosphorus Nuclear Magnetic Resonance Spectroscopy -31P NMR). We will also evaluate whether centrally administered k-opioid receptor agonists, microinjected into discrete brain cardioregulatory nuclei, exacerbate cardiovascular or brain metabolic dysfunction during shock. Finally, the therapeutic efficacy of two novel opioid antagonists, nalmefene and nor-binaltorphimine (which have increased activity at k sites), will be evaluated and compared to that of naloxone. 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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