The goal of this project is to elucidate the role of opioid peptides in the physiology and pathophysiology of posterior pituitary function. Specifically, the proposed studies will test the hypothesis that opioid interneurons are an integral part of the afferent pathways which mediates the effect of blood volume on vasopressin secretion. To this end, opioid antagonists specific for mu, delta or kappa receptors will be given to rats to determine if the antagonists alter the vasopressin response to osmotic, hemodynamic or glucopenic influences. To locate the receptors that mediate these effects, the antagonists also will be injected stereotaxically into brain ventricles to determine if blockage of opiate receptors in these areas reproduces the inhibition of specific vasopressin responses produced by systemic administration of the antagonists. The same opioid antagonists will be radiolabelled and used with autoradiography to determine specific in vivo binding sites. The effect of blood volume and other stimuli on the synthesis and/or secretion of individual opioid peptides in these regions will also be investigated using incorporation of radiolabelled aminoacids and radioimmunoassays specifically developed for this purpose. In these experiments, tissue will be obtained by punch biopsies of discrete brain areas and the peptides in questions will be extracted and identified by immunoassay as well as HPLC and Sephadex chromatography. Finally, to clarify their therapeutic potential, these antagonists will be given acutely and chronically to determine if they correct abnormalities in vasopressin secretion in animal models of diuretic abuse, cardiac and liver failure. The information obtained from these studies will help to clarify the role of endogenous opioids in brain function and may also provide a powerful new tool to treat s well as to define the pathogenesis of many clinical disorders of salt and water balance.
| Iwasaki, Y; Gaskill, M B; Robertson, G L (1995) Adaptive resetting of the volume control of vasopressin secretion during sustained hypovolemia. Am J Physiol 268:R349-57 |
| Iwasaki, Y; Gaskill, M B; Robertson, G L (1994) The effect of selective opioid antagonists on vasopressin secretion in the rat. Endocrinology 134:55-62 |
| Iwasaki, Y; Gaskill, M B; Boss, C A et al. (1994) The effect of the nonselective opioid antagonist diprenorphine on vasopressin secretion in the rat. Endocrinology 134:48-54 |
| Iwasaki, Y; Gaskill, M B; Fu, R et al. (1993) Opioid antagonist diprenorphine microinjected into parabrachial nucleus selectively inhibits vasopressin response to hypovolemic stimuli in the rat. J Clin Invest 92:2230-9 |
