Endogenous Opioid Peptide Regulation of Pulsatile Luteinizing Hormone Secretion during Pregnancy in the Rat

The objective of this study was to determine if endogenous opioid peptides (EOPs) influence the pattern of pulsatile luteinizing hormone (LH) secretion on days 6–8, 14–16 and 22 of gestation in the rat. Unanesthetized animals with two jugular cannulae were initially infused with 0.9% saline during which the control pattern of pulsatile LH release was determined. Possible EOP involvement was then determined by infusion of the EOP receptor antagonist naloxone. Plasma estradiol (E2) and progesterone (P) values increased between days 6–8 and 14–16. While plasma E2 values remained elevated through day 22, plasma P values declined by 90%. As previously reported, mean blood LH levels during the control period on day 22 were higher than on days 6–8 and 14–16 due to an increase in LH pulse frequency. At each stage of gestation naloxone infusion increased mean blood LH levels. This stimulatory action of naloxone was reduced in a dose-dependent fashion by simultaneous infusion with morphine, demonstrating that this effect is mediated via EOP receptors. There was no difference in the in vivo pituitary responsiveness to LH-releasing hormone (LHRH) between rats infused with saline or naloxone at any stage of pregnancy, demonstrating that the stimulatory effect of naloxone was not exerted at the pituitary level. Naloxone increased both the amplitude and frequency of pulsatile LH secretion on days 6–8, and stimulated frequency on days 14–16. The effect on amplitude could not be assessed on days 14–16 because too few rats exhibited pulsatile LH secretion prior to naloxone infusion. The increase in pulse frequency was similar on days 6–8 and 14–16. Although naloxone increased LH pulse amplitude and frequency on day 22, these increases were significantly less than those seen on days 6–8 and 14–16, respectively. Pituitary responsiveness to LHRH was less at all stages of pregnancy in comparison to responsiveness in ovariectomized rats, and progressively declined from days 6–8 through day 22. The lowest responsiveness to LHRH was seen on day 22 and contributed, at least in part, to the diminished increase in LH pulse amplitude in response to naloxone infusion on day 22 compared to days 6–8. The reduced naloxone-induced increment in LH pulse frequency on day 22, occurring coincident with a precipitous decline in plasma P levels, suggests a decreased EOP suppression of pulse frequency at this time. Since recent studies in our laboratory demonstrated that the increase in LH pulse frequency on day 22 is due to loss of the negative feedback action of P on pulsatile LH secretion, we postulate that during pregnancy P suppresses LH pulse frequency through an EOP-mediated mechanism, and as plasma P levels decline on day 22, EOP suppression of pulse frequency is diminished. The result is an increase in LH pulse frequency, and a diminished effect of naloxone on this parameter of pulsatile LH secretion.