Naloxone-induced increases in serum luteinizing hormone in the male: Mechanisms of action

Naloxone and its structurally related analog, naltrexone, increase serum luteinizing hormone (LH) levels in the male of several species. Since morphine has been shown to competitively antagonize the effects of naloxone on LH, it seems probable that naloxone increases LH by virtue of its opiate-receptor blocking properties. However, there are alternative, nonopiate-dependent mechanisms by which naloxone could increase serum LH. The present studies were carried out to examine the most plausible possibility: that naloxone displaces testosterone from its binding sites in the hypothalamus and pituitary and thereby relieves the hypothalamic-pituitary-LH axis of androgen-dependent negative feedback control. On the basis of our results, this hypothesis does not appear to be tenable since we have found that: 1) naloxone increased serum LH to the same extent in castrated male rats as it did in controls; 2) naloxone and naltrexone did not displace [³H] dihydrotestosterone from its cytosol binding proteins in the hypothalamus; 3) steroids did not compete with opiates for their binding sites in the hypothalamus; and 4) naloxone did not interfere with dihydrotestosterone's inhibition of LH-releasing hormone-stimulated LH production by the pituitary in vitro. On the basis of these observations. It does not appear that naloxone or naltrexone increases serum LH in the male rat by a testosterone-dependent mechanism. Rather, the results suggest, in agreement with earlier studies, that naloxone promotes the release of LH by blocking the effects of an as yet unidentified endogenous opioid ligand which normally inhibits the function of the hypothalamic-pituitary-LH axis.