naloxone and Hot-Flashes

Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg.d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 alpha-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg.d) dose dependently inhibited this effect. ICI (3.0 mg/kg.d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg.d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg.d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.

Topics: Animals; Blood-Brain Barrier; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Ethinyl Estradiol; Female; Fulvestrant; Hot Flashes; Hypothalamus; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Ovariectomy; Rats; Rats, Sprague-Dawley; Skin Temperature; Uterus

To evaluate the efficacy of estetrol (E(4)) in alleviating hot flushes in an experimental animal model considered representative for menopausal vasomotor symptoms.. Recording of the thermal responses in the tail skin of morphine-dependent ovariectomized rats after morphine withdrawal by administration of naloxone. Six groups of rats were treated orally for 8 days as follows: vehicle (negative) control; E(4): 0.1, 0.3, 1.0 and 3.0 mg/kg/day; and, as active (positive) control, ethinylestradiol 0.3 mg/kg/day. On day 8, tail skin temperature was recorded at baseline and for 60 min at 5-min intervals following naloxone administration. Results In control animals, tail skin temperature increased sharply by about 4.5 degrees C after naloxone treatment and reverted to baseline by 60 min. Estetrol suppressed the tail skin temperature increase in a dose-dependent fashion. The highest dose of E(4) tested (3 mg/kg/day) was equipotent to a 10-fold lower dose of ethinylestradiol. Both fully suppressed tail skin temperature changes.. Estetrol is effective in alleviating hot flushes in an experimental animal model considered representative for studying menopausal hot flushes (vasomotor symptoms). In this model, the potency of estetrol is 10-fold lower compared to ethinylestradiol.

Topics: Administration, Oral; Animals; Dose-Response Relationship, Drug; Estetrol; Female; Hot Flashes; Humans; Models, Animal; Models, Biological; Morphine; Naloxone; Ovariectomy; Random Allocation; Rats; Rats, Sprague-Dawley; Skin Temperature; Substance Withdrawal Syndrome

Thermoregulation is an integrated network of neuroendocrine, autonomic and somatosensory responses. Thermoregulatory dysfunction occurs during fluctuations or decline of gonadal hormone levels and results in vasomotor symptoms such as hot flushes and/or night-time sweating. The neurotransmitter serotonin (5-HT), has been reported to play a role in thermoregulation via changes in extracellular 5-HT levels and/or activation of various 5-HT receptors. The purpose of this study was to evaluate the role of the selective 5-HT reuptake inhibitor (SSRI), fluoxetine (FLX), on temperature regulation using ovariectomized (OVX) rodent models of thermoregulation. Single, subcutaneous (s.c.) administration of FLX (3, 10, 30 and 60 mg/kg) dose-dependently reduced core body temperature (CBT). FLX at 3 and 10 mg/kg s.c. showed no statistically significant decrease on tail-skin temperature (TST), whereas at higher doses (30 and 60 mg/kg) a significant decrease in TST was noted in the telemetry model. To mimic chronic SSRI treatment, a 5-HT(1A) antagonist (WAY-100635; 0.3 mg/kg) was administered 20 min prior to FLX (10 mg/kg). This combination showed no significant improvement on temperature dysfunction compared to FLX alone. Similarly, in a morphine-dependent model of temperature dysfunction FLX, was inactive at 10 mg/kg whereas the 30 and 60 mg/kg s.c. dose abated the naloxone-induced increase in TST by 55 and 81%, respectively. In summary, FLX affected CBT at all doses, but alleviated thermoregulatory dysfunction only at higher doses that are non-selective for the 5-HT system.

Topics: Animals; Body Temperature Regulation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Female; Fluoxetine; Hot Flashes; Morphine Dependence; Naloxone; Ovariectomy; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Antagonists; Telemetry

In our studies of the development of a novel class of selective estrogen receptor modulators, (+)-3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1'-indane]-5,5'-diol hydrochloride (1) was found to be an estrogen receptor ligand with beneficial effects in rat models for human hot flush. Moreover, 1 was found to have beneficial effects on lipid and bone metabolism while maintaining marginal effects on the uterus and breasts. These findings suggest that 1 would provide a new treatment for hot flush.

Topics: Animals; Bone Density; Breast Neoplasms; Cholesterol; Drug Evaluation, Preclinical; Estradiol; Female; Hot Flashes; Indans; Male; Morphine Dependence; Naloxone; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Skin Temperature; Spiro Compounds; Stereoisomerism; Tumor Cells, Cultured; Uterus