We have documented that morphine withdrawal in the rat results in a rapid rise in skin temperature (or """"""""flush"""""""") which is preceded by a transient increase in heart rate and LH secretion and is followed by a fall in body core temperature. The temporal organization of these responses and their magnitude are remarkably similar to the physiological alterations manifested by women during a hot flush episode. We have also demonstrated that clonidine and estrogens reduce the severity of the flush in this rat model which we developed to study the mechanisms of hot flush. We also can induce similar responses in naive animals by central administration of LHRH or induction of hypoglycemia. Due to the high incidence of this menopausal syndrome, the availability of an animal model would serve as a useful tool by which to evaluate the hormonal, and neuronal mechanism(s) that underlie this thermoregulatory disturbance and to evaluate mechanisms of therapeutic agents in treating this syndrome. We plan to utilize such methods as pharmacological manipulations (centrally and peripherally), temperature recordings, hormonal determinations, telemetry, in vitro vascular techniques, clinical studies, and tissue catecholamine levels to aid in the understanding of the development and therapeutic implications of various flush inducing agents. In particular, utilization of animal models will allow us to evaluate: i) the effects of steroid withdrawal on mechanisms which mediate the hot flush; ii) possible triggers for the hot flush such as ambient temperature and the effect of circadian rhythms on flush responses; iii) the relationship between alpha-adrenergic neurons and LHRH in a hot flush response; iv) the role of calcium in mediating the hot flush; v) the possible mechanism(s) of estrogen and clonidine therapy in alleviating the symptoms of the hot flush; vi) the role plasma glucose plays in the hot flush syndrome in the rat and in women; and vii) the direct vascular alterations that occur during a flush response induced by morphine withdrawal, administration of LHRH and hypoglycemic conditions. Collectively these proposed studies will allow for a more in depth evaluation of an animal model to study the mechanism(s) responsible for a flush response. Results obtained from these studies will allow us to elucidate both central and peripheral mechanisms by which the hot flush is manifested. The clinical and animal studies will provide information as to possible therapeutic management for this common thermoregulatory disturbance. Therefore, the research proposal could lend to significant contributions to the understanding of the pathogenesis of the hot flush and provide information on the mechanism(s) of current and new therapeutic manipulations for this menopausal syndrome.
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