Modulation of morphine physical dependence and discriminative stimulus effects by ovarian hormones: Role of estradiol

Ovarian hormones influence the activity of endogenous opioids, and exogenous administration of estradiol reduces opioid intake and opioid seeking in animal models of opioid reward and reinforcement. The purpose of this study was to examine the effects of ovarian hormones on the discriminative stimulus effects of morphine and naloxone-precipitated opioid withdrawal. To this end, separate groups of ovariectomized female rats were trained to discriminate the stimulus effects of either 3.0 or 10 mg/kg morphine, and substitution tests were conducted with estradiol or progesterone alone and in combination with morphine. At the conclusion of discrimination testing, rats were treated chronically with estradiol, progesterone, or their combination, and challenged with naloxone to measure opioid-like withdrawal symptoms. Finally, the effects of estradiol, progesterone, and their combination were examined on naloxone-precipitated withdrawal in morphine-dependent rats. Neither estradiol nor progesterone substituted for the morphine discriminative stimulus, but estradiol significantly increased the potency of morphine in rats trained to discriminate 10 mg/kg but not 3 mg/kg morphine. When administered chronically, neither hormone nor their combination produced an opioid-like withdrawal syndrome following a naloxone challenge. Acute administration of estradiol, but not progesterone or a combination of estradiol and progesterone, significantly reduced naloxone-precipitated weight loss in morphine-dependent rats. These data indicate that estradiol influences the behavioral effects of morphine, possibly by increasing endogenous tone at mu opioid receptors.