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 study demonstrated that the inhibitory effect was mediated by a kappa(2) opioid receptor. In the present study, the polyamine site antagonist ifenprodil converted dynorphin's biphasic concentration response relationship to a monophasic inhibitory curve. The polyamine diethylenetriamine also blocked dynorphin's excitatory actions. The combination of dynorphin 1-17 and naloxone produced neurotoxicity, presumably as a result of dynorphin's excitatory actions on NMDA receptors. In addition, the release of endogenous dynorphin from mossy fibers in the presence of naloxone injured the cells. Ifenprodil prevented the neurotoxicity of both applied and released dynorphin. These findings suggest that dynorphin acts at a polyamine site to produce its excitatory effects and, further, suggest that dynorphin may mediate some neuropathologies through its interaction at this site.