Activation of mu-opioid receptor selectively potentiates NMDA-induced outward currents in rat locus coeruleus neurons.

We investigated the opioid modulation of N-methyl-d-aspartic acid (NMDA) receptor-mediated response in dissociated LC neurons using nystatin-perforated patch recording. In Mg(2+)-free extracellular solution, NMDA induced an inward current (I(NMDA-IN)) and a subsequent outward current (I(NMDA-OUT)) at a holding potential of -40 mV. A selective mu-opioid receptor agonist, d-Ala(2),N-MePhe(4),Gly(5)-ol-enkephalin (DAMGO), potentiated I(NMDA-OUT) in a concentration-dependent manner with the half-maximal effective concentration of 0.7 microM, while DAMGO (0.1-10 microM) did not affect I(NMDA-IN). Under the condition of I(NMDA-OUT) blockade by the use of Cs-based pipette solution or by buffering intracellular Ca(2+) with a high concentration of EGTA and zero Ca(2+), DAMGO did not change I(NMDA-IN). The DAMGO potentiation of I(NMDA-OUT) was prevented by naloxone, an opioid receptor antagonist. In addition, the DAMGO potentiation of I(NMDA-OUT) was prevented by treatment with staurosporine, a broad spectrum protein kinase inhibitor. In conclusion, mu-opioid receptor activation selectively potentiated I(NMDA-OUT) via intracellular signal pathway without affecting I(NMDA-IN) in LC neurons. We suggest the inhibitory opioid effect through NMDA receptor-mediated response in LC neurons.