Slow Excitatory Phenomena - Interaction of Excitatory Amino Acids and Neuropeptides

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The perception of pain requires excitatory synaptic transmission from primary afferent sensory fibers to secondary projection neurons in the dorsal horn of the spinal cord. Two groups of neurotransmitter candidates are thought to mediate this initial excitatory step in the pain pathway: one being excitatory amino acids (EAA: glutamate, asparate), and another are peptides (including tachykinins such as substance P and neurokinin A). These peptides may be colocalized with an excitatory amino acid(s) in the same neurons. Chemical signal transfer via such neurons presents new aspects and complexities of presynaptic (synaptic efficacy) and postsynaptic (membrane excitability) regulation which have not previously been considered and may have important implications for the performance of the somatosensory, especially of pain pathways. Dr. Randic has recently found that substance P and excitatory amino acids interact to produce neurophysiological signs of hyperalgesia i.e. a prolonged enhancement of responses to excitatory manipulation. However, the sites and the molecular mechanisms by which the peptide signals produce enhanced EAA responses have yet to be elucidated. Dr. Randic will examine the hypothesis that the activation of distinct neurokinin receptors causes modulation of the responses of freshly isolated spinal dorsal horn neurons to EAAs, especially to N-methyl-D-aspartic- acid (NMDA). To gain understanding of molecular mechanism(s) underlying interactions between EAAs, and tachykinins possible involvement of glycine allosteric site of NMDA receptor channel complex, guanine nucleotide-binding proteins (G-proteins) or change in Ca++-sensitive second messenger systems, will be investigated. Whole-cell voltage-clamp recording of EAA responses will be utilized in this study. Delineating the cellular mechanism(s) of peptide actions on dorsal horn neurons is an important step toward understanding anatomical and neurochemical organization of the spinal dorsal horn.***//