Pulsatile
gonadotropin-releasing hormone (
GnRH) secretion is indispensable for reproduction in mammals.
Kisspeptin neurons in the hypothalamic arcuate nucleus (
ARC), referred to as KNDy neurons because of the coexpression of
neurokinin B and
dynorphin A, are considered as components of the
GnRH pulse generator that produces rhythmic
GnRH secretion. The present study aimed to investigate if peripheral administration of
PF-4455242, a κ-
opioid receptor (KOR, a
dynorphin A receptor) antagonist, facilitates pulsatile
luteinizing hormone (LH) secretion and
GnRH pulse generator activity in
estrogen-treated ovariectomized Shiba goats to determine the possibility of using KOR antagonists to artificially control ovarian activities.
PF-4455242 was intravenously infused for 4 h (1 or 10 μmol/kg
body weight/4 h) or as a single
subcutaneous injection (1 or 10 μmol/kg
body weight). In a separate experiment, the same KOR antagonist (10 μmol/kg
body weight/4 h) was intravenously infused during the recording of multiple unit activity (MUA) in the
ARC that reflects the activity of the
GnRH pulse generator to test the effects of KOR antagonist administration on
GnRH pulse generator activity.
Intravenous infusion and single
subcutaneous injection of the KOR antagonist significantly increased the frequency of LH pulses compared with controls.
Intravenous infusion of KOR antagonist also significantly increased the frequency of episodic bursts in the MUA. The present study demonstrates that peripherally administered KOR antagonist stimulates pulsatile LH secretion by acting on the
GnRH pulse generator, and peripheral administration of
PF-4455242 can be used to facilitate pulsatile LH secretion, which in turn facilitates ovarian activities in farm animals.