Phencyclidine (PCP) abuse is a major problem among the youth of this country, but we understand little of its mode of action in the CNS. This project will examine the involvement of PCP/Cross Section receptors as possible modulators of the spinal function of excitatory amino acids (EAAs) in the transmission of pain. This goal will be accomplished through electrophysiological, behavioral, receptor binding and autoradiographic studies. Although the spinal cord is likely not involved in the production of psychosis after repeated PCP abuse, understanding its spinal action may assist in analysis of its action in the brain. This project will also improve our understanding of the neurohumoral transmission and modulation of pain information through synapses between primary afferent sensory fibers and the spinal cord neurons that project to the brain. Such an understanding can enhance our ability to design analgesic drugs in the future. The spinal cord is a potentially more fruitful target for analgesics than other CNS locations because subsequent destinations for nociceptive information are diverse both anatomically and pharmacologically. This study will explicitly examine the nociceptive activity of ascending systems and their susceptibility to pharmacological modification. The electrical activity of single neurons with rostrally projecting axons will be identified using standard neurophysiological procedures. The effects of agents acting at EAA and/or PCP/Cross Section receptors on evoked activity will be determined after iontophoretic administration. The current literature suggests that some relation exists between receptors for PCP and the opioid receptors classified as o. A major goal of this study will be to ascertain if PCP/Cross Section binding the spinal cord represents one or more receptors. PCP/Cross Section binding sites in the spinal cord of the rat will be characterized using receptor binding techniques localized using autoradiographic techniques. We expect localization in areas of the spinal cord associated with nociceptive input and/or EAA receptors. Receptor binding experiments involving inhibition of NMDA displaceable 3H-L-glutamate by PCP/Cross Section agonists will address the hypothesis that compounds acting at PCP/Cross Section receptors may competitively inhibit binding to NMDA receptors in the spinal cord. We expect to find anatomical overlap between 3H-TCP, 3H-(+)-NAM and NMDA displaceable 3H-L-glutamate binding sites. Electrophysiological and behavioral studies will test the same compounds with maximum selectivity for each receptor class for excitation or inhibition of activity in ascending nociceptive neurons. These studies may reveal important information concerning the effects of, and treatment for, PCP abuse in humans.
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