BLOCKADE OF THE ESTROGEN-INDUCED LUTEINIZING-HORMONE SURGE IN OVARIECTOMIZED EWES BY A HIGHLY SELECTIVE OPIOID MU-RECEPTOR AGONIST - EVIDENCE FOR SITE OF ACTION

Endogenous opioid systems in the hypothalamus inhibit gonadotropin-rel easing hormone (GnRH) secretion, and a reduction in this inhibitory in put (disinhibition) is thought to be part of the neural mechanism of t he preovulatory GnRH/luteinizing hormone (LH) surge. We showed previou sly that intracerebroventricular infusion of the highly specific opioi d gamma-receptor agonist DAMGO delayed the oestrogen-induced LH surge in ovariectomized (OVX) ewes, whereas both delta- and kappa-agonists w ere ineffective. The aim of the present study was to establish the ana tomical site of this effect. The most likely hypothalamic sites of act ion 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 t he MPOA or the mediobasal hypothalamus (MBH), close to the ME, were in jected (im) with oestradiol benzoate (EB) 50 mu g (t = 0 h). In this m odel, EB elicits a time-delayed surge in LH secretion after 13-19 h. J ugular 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 mu-agonist DAMGO (40 nmol/h bilaterally) o r saline were given into the MPOA or MBH at 2.5 mu l/h. Guide tube pla cements were confirmed histologically. The mean (+/-SEM) time to the o nset of the LH surge was significantly (p < 0.01) increased in the ani mals (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 cle arly apparent in 6/9 of the DAMGO-infused animals. The mean (+/-SEM) t ime to LH surge onset was also significantly (p < 0.01) increased in t he 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 apparen t in 4/8 of the DAMGO-infused animals. We conclude that bilateral infu sion 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 hy pothalamic sites of opioid regulation of GnRH secretion, and are consi stent with the hypothesis that disinhibition from opioid tone at both the MPOA and MBH/ME is permissive of the preovulatory GnRHnH surge.