Role of KNDy neurons in the negative-feedback suppression of gonadotropin secretion in female rats.

The hypothalamic neurons that coexpress kisspeptin, neurokinin B, and dynorphin (KNDy) play a crucial role in the control of gonadotropin-releasing hormone (GnRH) pulsatile release and, thereby, in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. However, the feedback mechanism of sex steroids on KNDy neurons is not fully understood. We selectively ablated KNDy neurons using intra-arcuate nucleus injections of neurokinin-3 receptor agonist conjugated with saporin (NK3-SAP) to investigate their role in gonadotropin secretion in female rats under different feedback conditions. NK3-SAP rats bearing submaximal (75%) ablation of KNDy neurons displayed estrous cycle irregularity, an increased number of preovulatory follicles, and similar occurrence of corpora lutea. LH pulse frequency and amplitude, and basal LH and FSH levels were elevated in NK3-SAP rats on diestrus. Ovariectomy increased pulsatile LH secretion and basal LH and FSH levels, abolishing the differences between NK3-SAP and blank-SAP. In estradiol (E2)-treated ovariectomized (OVX + E2) rats, NK3-SAP ablation of KNDy neurons increased the frequency of the LH pulses but not basal gonadotropin secretion. Thus, the submaximal loss of KNDy neurons potentiates pulsatile LH secretion and increases basal LH and FSH release during negative-feedback states, in which E2 is required for LH pulse modulation. Supporting a dynorphin role, treatment of OVX + E2 rats with kappa-opioid receptor agonist, nor-binaltorphimine, increased basal and surge LH secretion, associated with a higher c-Fos expression in KNDy and GnRH neurons. Our findings provide evidence that KNDy neurons play a role in limiting pulsatile and nonpulsatile gonadotropin secretion during negative feedback, possibly through a dynorphin output.