Blockade of the Oestrogen-Induced Luteinizing Hormone Surge in Ovariectomized Ewes by a Highly Selective Opioid µ-Receptor Agonist: Evidence for Site of Action

Abstract

Endogenous opioid systems in the hypothalamus inhibit gonadotropin-releasing hormone (GnRH) secretion, and a reduction in this inhibitory input (disinhibition) is thought to be part of the neural mechanism of the preovulatory GnRH/luteinizing hormone (LH) surge. We showed previously that intracerebroventricular infusion of the highly specific opioid µ-receptor agonist DAMGO delayed the oestrogen-induced LH surge in ovariectomized (OVX) ewes, whereas both δ- and ĸ-agonists were ineffective. The aim of the present study was to establish the anatomical site of this effect. The most likely hypothalamic sites of action are the medial preoptic area (MPOA), where most GnRH perikarya are located in sheep, and/or the median eminence (ME), where GnRH fibres terminate on hypophysial portal blood vessels. Conscious, unrestrained OVX ewes with permanent bilateral guide tubes implanted into either the MPOA or the mediobasal hypothalamus (MBH), close to the ME, were injected (im) with oestradiol benzoate (EB) 50 µg (t = 0 h). In this model, EB elicits a time-delayed surge in LH secretion after 13–19 h. Jugular venous blood was sampled at half-hourly intervals from –2 to 0 h, and from 10 to 26 h. From 12 to 20 h, bilateral infusions of either the highly specific opioid µ-agonist DAMGO (40 nmol/h bilaterally) or saline were given into the MPOA or MBH at 2.5 µl/h. Guide tube placements were confirmed histologically. The mean (± SEM) time to the onset of the LH surge was significantly (p < 0.01) increased in the animals (n = 9) that received DAMGO infusion into the MPOA (20.5 ± 1.4 vs. 15.7 ± 0.6 h in the saline-infused controls). The effect was clearly apparent in 6/9 of the DAMGO-infused animals. The mean (± SEM) time to LH surge onset was also significantly (p < 0.01) increased in the animals (n = 8) that received DAMGO infusion into the MBH (19.7 ± 1.2 vs. 14.3 ± 0.5 h). In this case, the effect was clearly apparent in 4/8 of the DAMGO-infused animals. We conclude that bilateral infusion of DAMGO into either the MPOA or the MBH can delay the EB-induced LH surge in OVX ewes. These data provide further evidence for dual hypothalamic sites of opioid regulation of GnRH secretion, and are consistent with the hypothesis that disinhibition from opioid tone at both the MPOA and MBH/ME is permissive of the preovulatory GnRH/LH surge.

The Neurobiology of Preovulatory and Estradiol-Induced Gonadotropin-Releasing Hormone Surges

“…Concentrations of ␤-endorphin in the median eminence have been measured to be higher during the late follicular compared with early luteal phase (306) and correspondingly to show a progressive increase from the luteal to follicular phase (344). Moreover, infusion of ␤-endorphin into the posterior-lateral median eminence decreases both GnRH and LH release (344), and infusion of an opioid -receptor agonist into either the preoptic area or mediobasal hypothalamus delays LH surge onset (345). Measurements of POMC mRNA levels in the arcuate nucleus, however, either show no difference during the GnRH/LH surge compared with either the luteal phase or the portion of the follicular phase preceding the surge (346,347) or are increased at the peak of the LH surge in OVXϩE ewes compared with OVX controls (346).…”

Correlation between ovarian steroidogenesis and beta-endorphin in the Lizard Uromastyx acanthinura: Immunohistochemical approach.

“…Opioids affect this system mainly through the modulation of GnRH and LH secretion [1][2][3][4][5][6][7]. In addition, the β-endorphin participates to the control of reproductive function through a direct local action within reproductive tissues.…”

Steroid effects on the in vitro LH secretion from pituitary cells of sexually immature carp (Cyprinus carpio L.) under the influence of naltrexone and morphine

“…The reduction of this inhibition is necessary for the preovulatory surge of LH (Spijkstra et al, 1988;Walsh and Clarke, 1998). Gonadal steroids also exert an inhibitory effect on gonadotropin secretion (negative feedback action) and this effect is mediated (at least in part) by an increase in the opioidergic tone of the hypothalamus which is the cause of decreased GnRH secretion and a subsequent reduction of LH release (Ferin et al, 1984;Melis et al, 1984).…”