KAPPA(2) OPIOID RECEPTORS INHIBIT NMDA RECEPTOR-MEDIATED SYNAPTIC CURRENTS IN GUINEA-PIG CA3 PYRAMIDAL CELLS

The role of the endogenous opioid peptide dynorphin (1-17) in regulati ng NMDA receptor-mediated synaptic currents was examined in guinea pig hippocampus. Schaffer collateral/commissural fiber-evoked NMDA synapt ic currents were recorded using whole-cell patch-clamp techniques in C A3 pyramidal cells. Dynorphin was found to have dual effects on NMDA s ynaptic currents, increasing currents at low concentrations and decrea sing currents at high concentrations. Only the inhibitory action of dy norphin was sensitive to naloxone, indicating that this effect was med iated by an opioid receptor. The inhibitory effect was mimicked by bre mazocine, but not by U69,593, U50,488, [D-Ala(2), N-Me-Phe(4), Gly-ol] -enkephalin, or [D-Pen(2,5)]-enkephalin. Bremazocine's effect was bloc ked by naloxone, but not by nor-binaltorphimine, cyprodime, or naltrin dole. These findings suggest that bremazocine's effect was mediated by the kappa(2) subtype of opioid receptor. In addition, 1 mu M naloxone and antisera to dynorphin (1-17) were found to increase NMDA-mediated synaptic currents. Nor-binaltorphimine, cyprodime, naltrindole, and a ntisera to met-enkephalin did not increase the NMDA synaptic current. These findings suggest that endogenous dynorphin was acting at kappa(2 ) receptors to inhibit NMDA receptor-mediated synaptic currents. Overa ll, these findings indicate that dynorphin is an endogenous agonist fo r kappa(2) receptors in the CA3 region of the guinea pig hippocampus a nd that these receptors regulate NMDA receptor function.