The effect of estrogens and antiestrogens in rat models of hot flush

Abstract

AbstractRat models of hot flush provide important preclinical tools for evaluating the effect of estrogens and the selective estrogen receptor modulators (SERM), including tamoxifen, raloxifene, and tibolone, some of which have received renewed attention as agents to treat neurodegenerative diseases. The first rat model of hot flush is the ovariectomized morphine‐dependent model. When morphine is withdrawn with the opioid antagonist naloxone, temperature of the tail is increased by 4–6°C (“hot flush”). Estrogens reduce the elevation of tail skin temperature significantly. Tamoxifen functions as a partial agonist, whereas raloxifene functions as anti‐estrogen in this animal model. However, when co‐administered with estrogen, both tamoxifen and raloxifene antagonize estrogen's action. The second model is based on the diurnal change in tail skin temperature of intact rats, which is 6°C lower during the active phase (lights off) than in the passive phase (lights on) of the day. Ovariectomy affects tail skin temperature of the rats' active but not their passive phase, and skin temperature drops only 1°C instead of the 6°C measured in intact, cycling rats. Estrogen and tibolone restore the changes in tail skin temperature to that present in intact rats; however, raloxifene functions as anti‐estrogen in this model. Although neither of the two models exactly recapitulates the hot flush occurring in humans, the heat‐dissipating mechanisms are probably similar. Thus, both models can be used to evaluate the estrogenic versus anti‐estrogenic nature of estrogen receptor ligands, and both models, therefore, provide valuable preclinical tools for drug discovery aimed at identifying compounds to alleviate hot flushes in humans. Drug Dev. Res. 66:182–188, 2006. © 2006 Wiley‐Liss, Inc.