Modulation of the binding characteristics of hypothalamic mu opioid receptors in rats by gonadal steroids

Abstract

Recent evidence suggests that the effects of the opioids on gonadotropin release may depend on the endocrine status existing in the experimental animal. In the brain, the effects of the opioids are exerted through the interaction with different classes of opioid receptors (mu, delta, kappa, etc.). Among these, the mu receptors appear to be particularly relevant to the control of gonadotropin secretion. Different groups of experiments have been performed in the rat in order to analyze whether changes of circulalting levels of sex steroids may have an impact on the binding characteristics of hypothalamic mu opioid receptors, as evaluated by a receptor binding assay performed on plasma membrane preparations, using [ 3H]dihydromorphine as a mu ligand. In a first series of experiments, it has been observed that the ontogenesis of hypothalamic mu opioid receptors is different in male and in female rats: the concentration of mu sites, similar in animals of the two sexes at 16 days of age, increases in females, but not in males, between day 16 and day 26 of life. This sexual difference persists in 60-day old animals, when the brain is fully mature. It has also been observed that the pattern of maturation of hypothalamic mu receptors can be reversed by neonatal castration of males and by neonatal testosterone treatment of females. In a second series of experiments, it has been shown that in the hypothalamus of regularly cycling female rats the concentration of mu receptors varies during the different phases of the estrous cycle. In particular, a rather high density of mu sites during diestrus day 2 and the morning of the day of proestrus was found; this is followed by a progressive decline during the afternoon of the day of proestrus and the day of estrus, with a minimum value of the concentration of mu receptors being recorded in the first day of diestrus. These fluctuations seem to be linked to the physiological changes of serum levels of ovarian steroids: in fact, in a third series of experiments, it has been found that the positive feedback effect on LH release, exerted by the treatment of ovariectomized female rats with estrogens plus progesterone, is accompanied by a significant decrease of the concentration of hypothalamic mu opiod receptors; treatments with estrogens alone, able to induce a negative feedback effect on LH secretion, are not associated with modifications of hypothalamic mu receptors. These data seem to indicate that hypothalamic mu receptors may be involved in the positive but not in the negative feedback control of LH secretion. Finally, it has been observed that during pregnancy there is a significant increase of the concentration of hypothalamic mu opioid receptors followed by a return towards control levels during the postpartum period. On the other hand, the simulation of the levels of sex steroids present during the first half of pregnancy, obtained through a long-term treatment of ovariectomized animals with estrogens plus progesterone, was not accompanied by any modification of the concentration of hypothalamic mu receptors. On the basis of these last results, the authors would then be inclined to suggest that, during pregnancy, the concentration of hypothalamic mu opioid receptors is not linked to endocrine phenomena, but may be related to the stressful conditions represented by pregnancy itself and by the oncoming delivery. The present findings strongly suggest that, in particular conditions, a strict link may exist between the endocrine environment and the binding characteristics of mu opioid receptors at hypothalamic level.