Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus

Abstract

ALTHOUGH anatomical and neurochemical studies suggest that endogenous opioids act as neurotransmitters^1–7, their roles in normal and pathophysiological regulation of synaptic transmission are not defined. Here we examine the actions of prodynorphin-derived opioid peptides in the guinea-pig hippocampus and show that physiological stimulation of the dynorphin-containing dentate granule cells can release endogenous dynorphins, which then activate κ₁ opioid receptors present in the molecular layer of the dentate gyrus. Activation of κ₁ receptors by either pharmacologically applied agonist or endogenously released peptide reduces excitatory transmission in the dentate gyrus, as shown by a reduction in the excitatory postsynaptic currents evoked by stimulation of the perforant path, a principal excitatory afferent. In addition, released dynorphin peptides were found to block the induction of long-term potentiation (LTP) at the granule cell-perforant path synapse. The results indicate that endogenous dynorphins function in this hippocampal circuit as retrograde, inhibitory neurotransmitters.