The effect of blockade of kappa-opioid receptors in the medial preoptic area on the luteinizing hormone surge in the proestrous rat.

The present study examined whether blockade of kappa-opioid receptors in the medial preoptic area (MPOA) prior to the critical period on the afternoon of proestrus could prematurely evoke an ovulatory luteinizing hormone (LH) surge, and if so, whether norepinephrine (NE) is involved in mediating this response. In the first experiment, push-pull perfusion of the MPOA with nor-binaltorphimine (nor-BNI), a specific kappa-opioid receptor antagonist, was done in rats between 10.30 and 13.50 h on proestrus. To determine whether any resulting ovulation was due to a nor-BNI-induced increase in LH release, rats were injected with pentobarbital at 13.55 h to block the afternoon LH surge. In 7 of 10 rats, nor-BNI in the MPOA produced a large increase in LH release beginning between 12.30 and 13.30 h, and 5 of 7 ovulated. During MPOA perfusion with cerebrospinal fluid in our normal colony between 14.00 and 17.00 h, surges of LH release began in the majority of rats between 15.30 and 16.30 h. Thus blockade of MPOA kappa-opioid receptors advanced the LH surge by 3 h. The next experiment examined the effect of NE synthesis inhibition with bis(4-methyl-1-homopiperazinylthiocarbonyl) disulfide (FLA-63), or alpha-adrenergic receptor blockade with phenoxybenzamine (PBZ), on the nor-BNI-induced LH response. In 5 of 6 vehicle-treated rats, blockade of MPOA kappa-opioid receptors elicited a large increase in LH release and all 5 ovulated. In contrast, only 3 of 8 rats pretreated with FLA-63 had a large increase in LH release and ovulated, and PBZ prevented the nor-BNI-induced LH increase and ovulation in 4 of 4 rats. PBZ also prevented the afternoon LH surge and ovulation in 4 of 4 rats in our normal colony. Finally, HPLC measurement of NE levels in MPOA push-pull perfusate indicated no increase in NE release during the nor-BNI-induced or normal afternoon LH surges. These results indicate that antagonism of kappa-opioid receptors in the MPOA can prematurely evoke an ovulatory LH surge prior to the critical period on the afternoon of proestrus. Furthermore, the nor-BNI-induced as well as the normal afternoon LH surges are dependent on the proper functioning of central noradrenergic neurons, but do not involve increased NE release within the MPOA.