In vivo and in vitro Studies on the Opioidergic Control of the Secretion of Gonadotrophin-Releasing Hormone and Luteinizing Hormone in Sexually Immature and Adult Male Rats

Abstract

In vivo and in vitro methods have been used to compare the effects of opioid receptor blockade on the functional activity of the hypothalamo-pituitary-gonadal axis in adult (200 g) and sexually immature (50 g) male rats. In the adult, a single injection of the µ-receptor antagonist, naloxone (500 µg/100 g body weight, s.c), produced hypersecretions of luteinizing hormone (LH) and testosterone. Maximal serum concentrations of the two hormones were attained within 20 and 60 min respectively. In contrast, neither ICI 174864 (100 µg/100 g body weight, s.c.) nor MR2266 (150 µg/100 g body weight, s.c), which block δ- and ĸ-receptors respectively, stimulated pituitary-gonadal activity; indeed, like the saline vehicle, both tended to depress the serum LH concentration. The injection procedure was sufficient to activate the hypothalamo-pituitary-adrenal axis and, thus, the vehicle-treated controls exhibited significant increases in the plasma adrenocorticotrophin and serum corticosterone concentrations. These effects were enhanced by naloxone (500 µg/100 g body weight, s.c.) and by the ĸ-opioid receptor (MR2266, 150 µg/100 g body weight, s.c.) but not by the δ-opioid receptor antagonist (ICI 174864, 30–100 µg/100 g body weight, s.c). The increases in serum corticosterone and LH concentration induced by naloxone in adult rats were not apparent in the sexually immature (50 g) animals. To the contrary, in the young rats naloxone (250 and 500 µg/100 µg body weight, s.c.) attenuated, in a dose-dependent manner, the pronounced hypersecretion of corticosterone induced by the vehicle injection. The higher dose of the antagonist (500 µg/100 g body weight, s.c.) also overcame the significant reductions in serum LH evident 20 (p < 0.05) and 40 (p < 0.01) min after the saline injection but the lower dose (250 µg/100 g body weight, s.c.) was ineffective in this respect. In vitro, hypothalami from both adult and sexually immature rats responded to the addition of naloxone (10^–8–10^–6M) to the incubation medium with significant (p < 0.01) concentration-dependent increases in the release of gonadotrophin-releasing hormone (GnRH). In contrast, ICI 174864 (10"⁷–10^–6M) and MR2266 (10^-7–10^-6M) had little effect on the secretion of the releasing hormone by hypothalami from rats of either group although, at the highest concentration tested, MR2266 (10^–6M) precipitated a small increase in GnRH release from hypothalami from adult rats. The secretory responses of hypothalami from adult and prepubertal rats to naloxone were inhibited by the inclusion in the medium of the αi-adrenoceptor antagonist alfuzosin (10-⁶M) which, in the absence of naloxone, had no discernible effects on GnRH release. Receptor binding studies indicated that both the density and affinity of naloxone-sensitive opioid binding sites within the hypothalamus were similar in adult and sexually immature rats. The results demonstrate marked differences between the neuroendocrine responses of adul...

Immunoneutralization of Lipocortin 1 Reverses the Acute Inhibitory Effects of Dexamethasone on the Hypothalamo-Pituitary-Adrenocortical Responses to Cytokines in the Rat in vitro and in vivo

“…Our in vitro studies were based on a well-characterized hypothalamic preparation which has been used widely in studies on the mechanismscontrolling the release of CRF-41 and other releasing hormones [12,13,49], With regard to CRF-41. the data presented here confirm previous reports from our own [12,13] and other [50] laboratories that IL-la, IL-lp, IL-6 and IL-8 cause significant in creases in peptide release which are generally more pro nounced in tissue derived from adrenalectomized than intact rats [ 12. 13] and which are antagonized by preincubation of the tissue with dexamethasone within the time frame of the early-delayed feedback response [ 13].…”

Prepubertal increases in gonadotropin-releasing hormone mRNA, gonadotropin-releasing hormone precursor, and subsequent maturation of precursor processing in male rats.

“…First, the phenomenon be a stress-induced response to weaning, mediated by endogenous opiates that are known to affect GnRH release and pulsatility (55)(56)(57). Second, the increased GnRH gene transcription may be a temporal phenomenon dependent on a number of preceding developmental events.…”

Effects of DPDPE (a specific delta-opioid receptor agonist) and naloxone on hypothalamic monoamine concentrations during the pre-ovulatory LH surge in the rat

“…Previous reports have also shown that m-and k-opioid agonists not only reduce LH release at 1800 h, but also alter monoamine levels at 1430 h on the afternoon of pro-oestrus (9,11,(28)(29)(30). The findings on the role of d-receptors on LH release are conflicting (15,16).…”

“…]enkephalin; DPDPE) was seen to inhibit LH release in females (15), but a specific d-antagonist (ICI 154, 129) did not affect LH levels in males (16). The d-receptors have a more restricted distribution than the m-and k-receptors in the brain, and their density has been described as low to moderate in the rat hypothalamus with the highest levels located in the medial preoptic area (MPOA) and suprachiasmatic nucleus (SCN) (17,18).…”