Glucocorticoid feedback uncovers retrograde opioid signaling at hypothalamic synapses

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 report 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 (LTD(GABA)). LTD(GABA) is unmasked through glucocorticoid receptor inhibition of Regulator of G–protein Signaling 4 (RGS4), which amplifies signaling through postsynaptic metabotropic glutamate receptors (mGluRs). This drives 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 GC contributions to stress adaptation.