Regulation of arcuate neurons coexpressing kisspeptin, neurokinin B, and dynorphin by modulators of neurokinin 3 and κ-opioid receptors in adult male mice

Endocrinology. 2013 Aug;154(8):2761-71. doi: 10.1210/en.2013-1268. Epub 2013 Jun 6.


Pulsatile GnRH release is essential to fertility and is modulated by gonadal steroids, most likely via steroid-sensitive afferents. Arcuate neurons coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons) are steroid-sensitive and have been postulated to both generate GnRH pulses and mediate steroid feedback on pulse frequency. KNDy neurons are proposed to interact with one another via NKB and dynorphin to activate and inhibit the KNDy network, respectively, and thus alter kisspeptin output to GnRH neurons. To test the roles of NKB and dynorphin on KNDy neurons and the steroid sensitivity of these actions, targeted extracellular recordings were made of Tac2(NKB)-GFP-identified neurons from castrate and intact male mice. Single-cell PCR confirmed most of these cells had a KNDy phenotype. The neurokinin 3 receptor (NK3R) agonist senktide increased action potential firing activity of KNDy neurons. Dynorphin reduced spontaneous KNDy neuron activity, but antagonism of κ-opioid receptors (KOR) failed to induce firing activity in quiescent KNDy neurons. Senktide-induced activation was greater in KNDy neurons from castrate mice, whereas dynorphin-induced suppression was greater in KNDy neurons from intact mice. Interactions of dynorphin with senktide-induced activity were more complex; dynorphin treatment after senktide had no consistent inhibitory effect, whereas pretreatment with dynorphin decreased senktide-induced activity only in KNDy neurons from intact but not castrate mice. These data suggest dynorphin-mediated inhibition of senktide-induced activity requires gonadal steroid feedback. Together, these observations support the hypotheses that activation of NK3R and KOR, respectively, excites and inhibits KNDy neurons and that gonadal steroids modulate these effects.

Publication types

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

MeSH terms

  • Animals
  • Arcuate Nucleus of Hypothalamus / cytology
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Benzeneacetamides / pharmacology
  • Dynorphins / genetics
  • Dynorphins / metabolism*
  • Dynorphins / pharmacology
  • Gonadotropin-Releasing Hormone / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Kisspeptins / genetics
  • Kisspeptins / metabolism*
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Transgenic
  • Neurokinin B / genetics
  • Neurokinin B / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / physiology
  • Orchiectomy
  • Peptide Fragments / pharmacology
  • Pyrrolidines / pharmacology
  • Receptors, Neurokinin-3 / agonists
  • Receptors, Neurokinin-3 / genetics
  • Receptors, Neurokinin-3 / metabolism*
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / genetics
  • Receptors, Opioid, kappa / metabolism*
  • Substance P / analogs & derivatives
  • Substance P / pharmacology
  • Time Factors


  • Benzeneacetamides
  • Kisspeptins
  • Peptide Fragments
  • Pyrrolidines
  • Receptors, Neurokinin-3
  • Receptors, Opioid, kappa
  • senktide
  • Green Fluorescent Proteins
  • Substance P
  • Gonadotropin-Releasing Hormone
  • Dynorphins
  • Neurokinin B
  • U 69593