IFENPRODIL BLOCKS THE EXCITATORY EFFECTS OF THE OPIOID PEPTIDE DYNORPHIN-1-17 ON NMDA RECEPTOR-MEDIATED CURRENTS IN THE CA3 REGION OF THE GUINEA-PIG HIPPOCAMPUS

This study found that dynorphin had a biphasic concentration response relationship on N-methyl-D-aspartate (NMDA) receptor-mediated currents in the CA3 region of the guinea pig hippocampal slice. A previous stu dy demonstrated that the inhibitory effect was mediated by a kappa(2) opioid receptor. In the present study, the polyamine site antagonist i fenprodil converted dynorphin's biphasic concentration response relati onship to a monophasic inhibitory curve. The polyamine diethylenetriam ine also blocked dynorphin's excitatory actions. The combination of dy norphin 1-17 and naloxone produced neurotoxicity, presumably as a resu lt of dynorphin's excitatory actions on NMDA receptors. In addition, t he release of endogenous dynorphin from mossy fibers in the presence o f naloxone injured the cells. Ifenprodil prevented the neurotoxicity o f both applied and released dynorphin. These findings suggest that dyn orphin acts at a polyamine site to produce its excitatory effects and, further, suggest that dynorphin may mediate some neuropathologies thr ough its interaction at this site.