We have recently demonstrated that in the morphine (MORP)-dependent rat, naloxone (NAL)-induced withdrawal is accompanied by a dose-dependent, tail skin temperature (TST) increase of 4 to 7C (i.e. a hot flush). This rat hot flush is closely associated with a dramatic increase in LH secretion and an acceleration in heart rate. All three of these responses in the rat are remarkably similar in magnitude, duration and temporal organization to those observed in women during the menopausal hot flush. In the present grant application we will further evaluate the appropriateness of this animal model for the menopausal hot flush and use this model to elucidate the neuronal and endocrine mechanisms which mediate this common disorder in thermoregulation. Using methods for continuous monitoring of TST, rectal temperature (Tr) and heart rate and repeated blood sampling for LH determination by radioimmunoassay, we will define the brain loci which mediate the rat hot flush and associated autonomic alterations by microinjection of NAL into various brain regions. Additionally, we will evaluate the role of luteinizing hormone-releasing hormone (LHRH) in the series of neuronal events leading to the hot flush by local application of LHRH agonists and antagonists into the preoptic area medialis (POAm) of these MORP-dependent rats. To define the neuronal system involved in the rat hot flush alpha- and beta-adrenergic agonists and antagonists, as well as dopamine agonists and antagonists will be microinjected into the POAm in an attempt to induce the hot flush or to block the TST response to systemic NAL treatment. A further evaluation of the neuronal systems involved in the rat hot flush will utilize: (i) a determination of norepinephrine and dopamine metabolism in the POA and medial basal hypothalamus during the rat hot flush; and (ii) surgical destruction of the noradrenergic innervation of these two brain regions. The role of sex steroids in the rat hot flush will be assessed by evaluation of TST response to ovariectomy or ovariectomy plus adrenalectomy. Additionally, we will attempt to precipitate hot flushes in the rat by chronic exposure to estradiol followed by its precipitous withdrawal. Collectively, these studies will help to define the neuroendocrine mechanisms which mediate the hot flush in our animal model and may provide the basis for further evaluation of the pathogenesis of the hot flush in women and for alternative therapy for this common menopausal syndrome.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Biochemical Endocrinology Study Section (BCE)
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University of Florida
Schools of Pharmacy
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