Blockade of ovulation by methadone in the rat: a central nervous system-mediated acute effect

Morphine blocks ovulation in the rat and is associated with irregular menstrual cycles in humans. Methadone, the synthetic narcotic used to treat heroin addiction, was tested in rats for its ability to block ovulation. Equal doses of methadone were administered subcutaneously at 13:00, 14:00 and 15:00 hr on proestrus. Three different total (cumulative) doses were tested: 6, 9 and 15 mg/kg, in Wistar and Sprague-Dawley rats. The 6 mg/kg dose was ineffective, 9 mg/kg affected by Sprague-Dawley, whereas the 15 mg/kg dose blocked ovulation in both strains. Injection of saline at 13:00, 14:00 and 15:00 hr, or of the narcotic antagonist naltrexone at 12:00 had no effect on ovulation. Naltrexone prevented the blockade of ovulation by methadone, implicating narcotic receptors in the mediation of this action of methadone. Electrochemical stimulation of the medial preoptic area of the brain, or administration of exogenous luteinizing hormone overcame methadone's blockade of ovulation suggesting that the drug is acting via the central nervous system. The results of these studies suggest that menstrual dysfunction may not be a major problem in the clinical application of methadone.