Electrophysiological studies of cultured dorsal root ganglion (DRG) cells suggest that approximately 80% of DRG neurons utilize excitatory amino acids (EAA) as neurotransmitters. Recently our laboratory has raised a monoclonal antibody specific for fixative-modified glutamate. Using this antibody, immunoreactivity was observed within the spinal trigeminal nucleus (STN), spinal cord dorsal horn and dorsal root ganglia neurons, areas known to be involved in nociception. Based on these preliminary immunohistochemical data and other results from our laboratory showing apparent glutamatergic projections from the STN to the thalamus, we hypothesize that neurons in pathways involved in nociception utilize EAAs as neurotransmitters. Furthermore, their activity may be affected by substances which are known to alter nociception, such as opioids. Our long term goal is to determine whether EAAs play a role in primary afferent and/or centrally projecting fibers involved in pain transmission and whether these EAA pathways are specifically affected by opioid and non-opioid compounds. This goal is defined by the following specific objectives: 1) to characterize the distribution of glutamate- and aspartate-like immunostaining in the DRG and spinal cord, to analyze the relationship between opioid axon terminals and EAA-containing neurons, and to ascertain if spinal EAA-containing neurons project to the thalamus; 2) to compare using HPLC analysis as well as immunostaining, the concentrations of glutamate, aspartate and other EAAs in specific areas of the spinal cord before and after dorsal rhizotomy; 3) to measure the release of EAAs from spinal tissue into CSF following peripheral nerve stimulation and injection of opioid and non-opiate compounds which are known to alter either sensory-perception or EAA activity; 4) to determine the effect of a variety of recently developed EAA-analogs on nociception, as measured by methods which selectively elicit nociception using thermal, mechanical or chemical stimuli. These studies will provide important and novel data on the role of EAAs in the spinal cord and the involvement of sigma opioid agonists in antinociception, perhaps involving blockade of EAA action.
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