Glucocorticoid feedback uncovers retrograde opioid signaling at hypothalamic synapses

Nat Neurosci. 2013 May;16(5):596-604. doi: 10.1038/nn.3374. Epub 2013 Apr 7.


Stressful experience initiates a neuroendocrine response culminating in the release of glucocorticoid hormones into the blood. Glucocorticoids feed back to the brain, causing adaptations that prevent excessive hormone responses to subsequent challenges. How these changes occur remains unknown. We found that glucocorticoid receptor activation in rodent hypothalamic neuroendocrine neurons following in vivo stress is a metaplastic signal that allows GABA synapses to undergo activity-dependent long-term depression (LTDGABA). LTDGABA was unmasked through glucocorticoid receptor-dependent inhibition of Regulator of G protein Signaling 4 (RGS4), which amplified signaling through postsynaptic metabotropic glutamate receptors. This drove somatodendritic opioid release, resulting in a persistent retrograde suppression of synaptic transmission through presynaptic μ receptors. Together, our data provide new evidence for retrograde opioid signaling at synapses in neuroendocrine circuits and represent a potential mechanism underlying glucocorticoid contributions to stress adaptation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / metabolism*
  • Animals
  • Animals, Newborn
  • Bacterial Proteins / genetics
  • Channelrhodopsins
  • Enzyme Inhibitors / pharmacology
  • Feedback, Physiological / physiology*
  • Glucocorticoids / metabolism*
  • Hypothalamus / cytology*
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology
  • Luminescent Proteins / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurotransmitter Agents / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / deficiency
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Opioid, mu / genetics
  • Signal Transduction / physiology*
  • Stress, Psychological / blood
  • Stress, Psychological / pathology
  • Synapses / genetics
  • Synapses / physiology*
  • Vesicular Inhibitory Amino Acid Transport Proteins / genetics


  • Analgesics, Opioid
  • Bacterial Proteins
  • CNR1 protein, mouse
  • Channelrhodopsins
  • Enzyme Inhibitors
  • Glucocorticoids
  • Luminescent Proteins
  • Neurotransmitter Agents
  • Oprm protein, mouse
  • Receptor, Cannabinoid, CB1
  • Receptors, Glucocorticoid
  • Receptors, Opioid, mu
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • Viaat protein, mouse
  • yellow fluorescent protein, Bacteria