Chronic pain differs from acute pain in that it serves no protective or biological function. while clinical symptoms differ between acute and chronic pain, the underlying neurochemical and neuroanatomical differences are not well understood. Almost nothing is known regarding potential changes that may be occuring in the brain stem as pain becomes chronic. Because of the importance of this region not only to pain transmission but more importantly to pain modulation, the long term goal of these studies is to examine whether the basic biosynthetic metabolism of neurochemicals, their concentration in the brain, or the release of these neurochemicals in the PAG and other brain stem nuclei are affected by chronic pain. The studies proposed in this application will employ a polyarthritic rat chronic pain model to achieve three specific aims: 1) examine by in situ hybridization whether chronic pain causes selective changes in neuropeptide mRNA levels, 2) determine if chronic pain causes selective changes in the distribution and/or staining intensity of immunohistochemically identified neurons, and 3) analyze by in vivo microdialysis whether chronic pain causes changes in the extracellular concentrations of GABA, or any of the neuropeptides under study (beta- endorphin, dynorphin, enkephalins, substance P, and neurotensin). Novel techniques of in situ hybridization have been developed, employing fluorescence detection of biotinylated cDNA oligonucleotides. Hybridization experiments now require only a single day, instead of a month or more, required for neuropeptide mRNA autoradiography. Much more hybridization data can now be obtained, permitting major surveys of mRNA levels in disease states and permitting extensive correlations with immunocytochemical data. Electrical or pharmacologic stimulation in many areas within the brain can produce antinociception, but it is not clear which of them actually function in the normal response to acute or chronic pain. In the arthritic rat, brain regions that may contain peptide-and/or GABA-coded circuits that participate in the descending inhibition of spinal nociceptors will be examined. Those areas include the caudal hypothalamus, ventral striatal regions, the periaqueductal gray, and the rostroventral medulla. Based on any changes in the neuroanatomical distributions of mRNA and peptide levels within these regions, in vivo microdialysis will be performed to determine whether the changes, suggestive of altered biosynthetic activity, are accompanied by changes in peptide release. These neurochemical results, correlated with the neuroanatomical results, will address many unanswered questions regarding the differential effects of chronic versus acute pain on populations of peptidergic neurons.
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