Both Estrogen and Androgen Modify the Response to Activation of Neurokinin-3 and κ-Opioid Receptors in Arcuate Kisspeptin Neurons From Male Mice

Endocrinology. 2016 Feb;157(2):752-63. doi: 10.1210/en.2015-1688. Epub 2015 Nov 12.


Gonadal steroids regulate the pattern of GnRH secretion. Arcuate kisspeptin (kisspeptin, neurokinin B, and dynorphin [KNDy]) neurons may convey steroid feedback to GnRH neurons. KNDy neurons increase action potential firing upon the activation of neurokinin B receptors (neurokinin-3 receptor [NK3R]) and decrease firing upon the activation of dynorphin receptors (κ-opioid receptor [KOR]). In KNDy neurons from intact vs castrated male mice, NK3R-mediated stimulation is attenuated and KOR-mediated inhibition enhanced, suggesting gonadal secretions are involved. Estradiol suppresses spontaneous GnRH neuron firing in male mice, but the mediators of the effects on firing in KNDy neurons are unknown. We hypothesized the same gonadal steroids affecting GnRH firing pattern would regulate KNDy neuron response to NK3R and KOR agonists. To test this possibility, extracellular recordings were made from KNDy neurons in brain slices from intact, untreated castrated or castrated adult male mice treated in vivo with steroid receptor agonists. As observed previously, the stimulation of KNDy neurons by the NK3R agonist senktide was attenuated in intact vs castrated mice and suppression by dynorphin was enhanced. In contrast to observations of steroid effects on the GnRH neuron firing pattern, both estradiol and DHT suppressed senktide-induced KNDy neuron firing and enhanced the inhibition caused by dynorphin. An estrogen receptor-α agonist but not an estrogen receptor-β agonist mimicked the effects of estradiol on NK3R activation. These observations suggest the steroid modulation of responses to activation of NK3R and KOR as mechanisms for negative feedback in KNDy neurons and support the contribution of these neurons to steroid-sensitive elements of a GnRH pulse generator.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Androgens / pharmacology*
  • Animals
  • Arcuate Nucleus of Hypothalamus
  • Dihydrotestosterone / pharmacology*
  • Dynorphins / metabolism
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / agonists
  • Estrogen Receptor beta / agonists
  • Estrogens / pharmacology*
  • Gonadotropin-Releasing Hormone
  • Kisspeptins / metabolism*
  • Male
  • Mice
  • Neurokinin B / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Orchiectomy
  • Patch-Clamp Techniques
  • Peptide Fragments / pharmacology
  • Receptors, Neurokinin-3 / agonists*
  • Receptors, Opioid, kappa / agonists*
  • Receptors, Steroid / agonists
  • Substance P / analogs & derivatives
  • Substance P / pharmacology


  • Androgens
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Estrogens
  • Kisspeptins
  • Peptide Fragments
  • Receptors, Neurokinin-3
  • Receptors, Opioid, kappa
  • Receptors, Steroid
  • Dihydrotestosterone
  • senktide
  • Substance P
  • Gonadotropin-Releasing Hormone
  • Estradiol
  • Dynorphins
  • Neurokinin B