Alleviation of thermoregulatory dysfunction with the new serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized rodent models.
Hot flushes and night sweats, referred to as vasomotor symptoms (VMS), are presumed to be a result of declining hormone levels and are the principal menopausal symptoms for which women seek medical treatment. To date, estrogens and/or some progestins are the most effective therapeutics for alleviating VMS; however, these therapies may not be appropriate for all women. Therefore, nonhormonal therapies are being evaluated. The present study investigated a new reuptake inhibitor, desvenlafaxine succinate (DVS), in animal models of temperature dysfunction. Both models used are based on measuring changes in tail-skin temperature (TST) in ovariectomized (OVX) rats. The first relies on naloxone-induced withdrawal in morphine-dependent (MD) OVX rats, resulting in an acute rise in TST. The second depends on an OVX-induced loss of TST decreases during the dark phase as measured by telemetry. An initial evaluation demonstrated abatement of the rise in TST with long-term administration of ethinyl estradiol or with a single oral dose of DVS (130 mg/kg) in the MD model. Further evaluation showed that orally administered DVS acutely and dose dependently (10-100 mg/kg) abated a naloxone-induced rise in TST of MD rats and alleviated OVX-induced temperature dysfunction in the telemetry model. Oral administration of DVS to OVX rats caused significant increases in serotonin and norepinephrine levels in the preoptic area of the hypothalamus, a key region of the brain involved in temperature regulation. These preclinical studies provide evidence that DVS directly impacts thermoregulatory dysfunction in OVX rats and may have utility in alleviating VMS associated with menopause.
Deecher
Darlene C
DC
Women's Health and Musculoskeletal Biology, Wyeth Research N3164, 500 Arcola Road, Collegeville, PA 19426, USA. deeched@wyeth.com
Alfinito
Peter D
PD
Leventhal
Liza
L
Cosmi
Scott
S
Johnston
Grace H
GH
Merchenthaler
Istvan
I
Winneker
Richard
R
D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D003511:Cyclohexanols / Q000008:administration & dosage / Q000494:pharmacology*; D000069468:Desvenlafaxine Succinate; D004353:Drug Evaluation, Preclinical; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D023421:Models, Animal; D009021:Morphine Dependence / Q000473:pathology; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D010052:Ovariectomy; D011301:Preoptic Area / Q000737:chemistry / Q000187:drug effects; D051381:Rats; D012702:Serotonin Antagonists / Q000494:pharmacology; D013686:Telemetry
D000317:Adrenergic alpha-Antagonists; D003511:Cyclohexanols; D012702:Serotonin Antagonists; D004997:Ethinyl Estradiol; D009638:Norepinephrine; D000069468:Desvenlafaxine Succinate