Blockade of the oestrogen-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-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 mu-receptor agonist DAMGO delayed the oestrogen-induced LH surge in ovariectomized (OVX) ewes, whereas both delta- and kappa-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 (i.m.) with oestradiol benzoate (EB) 50 microg (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 mu-agonist DAMGO (40 nmol/h bilaterally) or saline were given into the MPOA or MBH at 2.5 microl/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.