Analysis of estradiol-independent and -dependent endogenous opioid peptide suppression of pulsatile LH release between the mornings of diestrus 2 and proestrus in the rat estrous cycle

Abstract The aim of this study was to analyze possible estradiol (E 2 )-independent and -dependent endogenous opioid peptide (EOP) suppression of pulsatile LH release between the mornings of diestrus 2 (D2) and proestrus by examining the LH response to naloxone infusions in the presence or absence of proestrous levels of E 2 . Pulsatile LH secretion remained unchanged between D2 and proestrus but mean blood LH levels, pulse amplitude and frequency increased within 24 hr following ovariectomy on D2. This increase was due in large part to the loss of E 2 negative feedback, since restoration of physiological proestrous E 2 levels returned LH pulse frequency to proestrous a.m. levels and greatly reduced pulse amplitude. In ovariectomized rats lacking E 2 negative feedback, continuous infusion of the EOP receptor antagonist naloxone (0.5 and 2 mg/kg/hr) caused a further increase in pulse amplitude and frequency. This naloxone-induced increment in pulsatile LH release was exerted via centrally located EOP receptors since naloxone did not alter pituitary responsiveness to LHRH, and its stimulatory action on pulsatile release was diminished by simultaneous infusion with morphine. Naloxone also increased pulsatile LH release in E 2 -treated animals. The naloxone-induced increments in LH pulse amplitude were the same in the presence or absence of E 2 negative feedback. Moreover, the increments in amplitude produced by naloxone in E 2 -treated rats were significantly less than those resulting from the combination of ovariectomy plus naloxone infusion in empty capsule-implanted rats. These data indicated that naloxone infusion in E 2 -implanted animals blocked an E 2 -independent EOP suppression of this parameter of pulsatile release. In contrast, with both naloxone doses tested, there was a trend for naloxone-induced increments in pulse frequency to be larger in ovariectomized rats previously implanted with E 2 rather than empty capsules. Although these differences were not statistically significant, the naloxone-induced increments in pulse frequency in E 2 -treated rats (unlike those in pulse amplitude) were large enough so that they were also significantly different from the overall increases in pulse frequency caused by the combination of ovarian steroid removal coupled with blockade of EOP receptors during naloxone infusion in empty capsule-implanted animals. This raises the possibility that naloxone infusions in E 2 -treated rats compromised both an E 2 -independent EOP suppression of pulse frequency and a small, E 2 -dependent component as well. Overall, the data demonstrate that between the mornings of D2 and proestrus, EOPs act independent of E 2 to suppress both LH pulse amplitude and frequency, and the negative feedback of E 2 on LH pulse amplitude is not mediated by EOPs whose receptors are antagonized by naloxone. The data also suggest the possibility that E 2 suppression of pulse frequency may be mediated, at least in part, by EOPs.