We have documented that morphine withdrawal is the rat results in a rapid rise in skin temperature. This 'flush' is preceded by a transient increase in heart rate, a 10-fold increase in LH secretion and is followed by a fall in core temperature. Each of these physiological responses are similar in magnitude and temporal organization to those observed in menopausal women undergoing a hot flush. We also have demonstrated that administration of estrogens or clonidine are effective in significantly reducing the rise in skin temperature in our rat model to study the mechanisms of the hot flush syndrome. The major objectives of the present grant application are to further define, in specific detail: (i) the relationship between brain dopaminergic and noradrenergic systems with the LHRH neuronal activity that is altered during the hot flush response; (ii) the role of the adrenal gland and the peripheral vasculature alterations that occur during a hot flush episode; (iii) the mechanism by which estrogen attenuates a hot flush response in the morphine-dependent rat; and (iv) define the role of acute hypoglycemia in the hot flush. Central administration of selective adrenergic and dopaminergic agonists or antagonists alone and in combination with either central administration of LHRH agonists or antagonists will be utilized in experiments to evaluate the relationship between the dopaminergic system and the LHRH neuron in mediating a flush response and the related physiologic responses. Additionally, more detailed experiments will be performed (including in vitro vascular studies) to evaluate the effective dose/duration of estrogen treatment and to dissociate central from peripheral effects of estrogen. Adrenalectomy abolished the TST response in the morphine-dependent rat, and hence several experiments will be performed to evaluate the role of both adrenal steroids and catecholamines in our animal model to study the mechanism of the hot flush. Finally, since we have observed in rats and women that flushes are associated with hypoglycemia, we will perform studies to evaluate the role of plasma glucose in mediating the hot flush response. Collectively, these studies will further define the central neuroendocrine mechanisms that initiate a flush response and define the role of peripheral systems. (adrenal, blood glucose and vascular tissue) in producing symptoms of the flush response. Therefore the research proposed may make significant contributions to our understanding of the pathogenesis of the hot flush and provide information to aid in the development of alternative therapy for this menopausal syndrome.
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