This project focused on the regulation of the N-methyl-D-aspartate (NMDA) peptide dynorphin. We demonstrated in the guinea pig hippocampal slice preparation that dynorphin can act as an agonist at two distinct receptors to regulate the function of NMDA receptors. The first site that dynorphin acts at in the hippocampal slice are the kappa2 opioid receptors. Dynorphin binding to this site results in an inhibition of the current that flows through the NMDA receptors. Prior to this discovery there was no known physiological function for the kappa2 opioid receptor. The second site that dynorphin acts at is the polyamine binding site located on the NMDA receptor. When dynorphin binds to this site the current flowing through the NMDA receptor is enhanced. The enhancement of the NMDA receptor-mediated current by dynorphin often results in neuronal damage and death in vitro. This finding is similar to the effect observed when dynorphin is injected onto the spinal cord of rats in vivo, suggesting that dynorphin's neurotoxic effects in vivo are mediated through the polyamine site of the NMDA receptor. It is well established that excessive activity in NMDA receptors may result in many different neuropathologies, including chronic pain. It is also well established that many of these pathologies are associated with elevated levels of endogenous dynorphin. Therefore, it is possible that endogenous dynorphin may play a role in enhancing the activity of NMDA receptors during pain. We are testing our hypothesis in a behavioral model of persistent pain. In rats whose right hind paw is inflamed by the injection of complete Freund's adjuvant, opioid agonists which act at the kappa2 opioid receptor inhibit the inflammation induced hyperalgesia when injected onto the spinal cord. The sensory profile of the non-inflamed paws are not altered by the kappa2 agonists. This finding is in contrast with the effects of other opioid agonists which alter the sensory profile of both the inflamed and the non-inflamed paws. The findings do, however, resemble results obtained by the injection of NMDA receptor antagonists, suggesting that the kappa2 receptors in vivo are regulating the NMDA receptors. Future work will focus on determining the mechanism by which kappa2 opioid receptors inhibit NMDA receptors and on the further characterization of the kappa2 opioid receptors and the polyamine binding site in the behavioral model.
