Retrograde opioid signaling regulates glutamatergic transmission in the hypothalamus.

Opioid signaling in the CNS is critical for controlling cellular excitability, yet the conditions under which endogenous opioid peptides are released and the precise mechanisms by which they affect synaptic transmission remain poorly understood. The opioid peptide dynorphin is present in the soma and dendrites of vasopressin neurons in the hypothalamus and dynamically controls the excitability of these cells in vivo. Here, we show that dynorphin is released from dendritic vesicles in response to postsynaptic activity and acts in a retrograde manner to inhibit excitatory synaptic transmission. This inhibition, which requires the activation of kappa-opioid receptors, results from a reduction in presynaptic release of glutamate vesicles. The opioid inhibition is downstream of Ca(2+) entry and is likely mediated by a direct modulation of presynaptic fusion machinery. These findings demonstrate that neurons may self-regulate their excitability through the dendritic release of opioids to inhibit excitatory synaptic transmission.