The focus of this study is the pharmacology and physiology of neuropeptides in the central nervous system. Experiments were carried out to A) characterize the effects of the endogenous opioid peptide dynorphin on hippocampal pyramidal cells and spinal neurons and B) characterize the effects of mu opioids on a newly discovered p300 like potential in the rat hippocampal slice preparation. In the CA3 region of the guinea pig hippo-campus we discovered that dynorphin has dual effects on NMDA synaptic currents. At low concentrations the NMDA current is increased and at high concentrations the current is decreased. The inhibitory effect is mediated by the kappa2 subtype of opioid receptor. This is the first demonstration of a physiological function for this receptor. The significance of this discovery is that NMDA receptors are known to mediate chronic pain in the spinal cord and that kappa2 receptors and spinal NMDA receptors are found in the superficial spinal dorsal horn. Thus, the kappa2 receptors represent a novel target for the inhibition of NMDA receptors in the treatment of pain. The receptor mediating the excitatory effect of dynorphin has not been determined yet. Future study of the excitatory action should lead to another novel target for pain management. An in vitro rat spinal cord slice preparation was developed. We have found that low concentrations of dynorphin increase the NMDA current in this preparation. High concentrations have not yet been tested. Future work in the spinal cord preparation will focus on the kappa2/NMDA interaction. We have discovered an extracellular potential in the CA1 region of the rat hippocampal slice that resembles the p300 in human EEG studies. Addition of mu selective agonists reduces the amplitude of this potential. The amplitude of the p300 is highly correlated with the ability of a subject to perceive information and pain management often exploits drugs that alter perception. Thus, this p300 like potential offers an in vitro method to study drugs that may alter perception of painful stimuli. Future work will focus on pharmacological characterization of this potential.
