The Roles of Neurokinins and Endogenous Opioid Peptides in Control of Pulsatile LH Secretion

Work over the last 15 years on the control of pulsatile LH secretion has focused largely on a set of neurons in the arcuate nucleus (ARC) that contains two stimulatory neuropeptides, critical for fertility in humans (kisspeptin and neurokinin B (NKB)) and the inhibitory endogenous opioid peptide (EOP), dynorphin, and are now known as KNDy (kisspeptin-NKB-dynorphin) neurons. In this review, we consider the role of each of the KNDy peptides in the generation of GnRH pulses and the negative feedback actions of ovarian steroids, with an emphasis on NKB and dynorphin. With regard to negative feedback, there appear to be important species differences. In sheep, progesterone inhibits GnRH pulse frequency by stimulating dynorphin release, and estradiol inhibits pulse amplitude by suppressing kisspeptin. In rodents, the role of KNDy neurons in estrogen negative feedback remains controversial, progesterone may inhibit GnRH via dynorphin, but the physiological significance of this action is unclear. In primates, an EOP, probably dynorphin, mediates progesterone negative feedback, and estrogen inhibits kisspeptin expression. In contrast, there is now compelling evidence from several species that kisspeptin is the output signal from KNDy neurons that drives GnRH release during a pulse and may also act within the KNDy network to affect pulse frequency. NKB is thought to act within this network to initiate each pulse, although there is some redundancy in tachykinin signaling in rodents. In ruminants, dynorphin terminates GnRH secretion at the end of pulse, most likely acting on both KNDy and GnRH neurons, but the data on the role of this EOP in rodents are conflicting.