Pain is a debilitating complication during chronic inflammation, such as arthritis, and difficult to treat for long periods of time. We hypothesize that elevated glutamate release from sensory nerves is responsible, in part, for the enhanced pain sensitivities of chronic inflammation. We have discovered in a rat model of chronic inflammation that sensory nerves in skin/joints produce large amounts of glutamate and its synthetic enzyme, glutaminase. Chronic inflammation causes increased production of glutaminase in the neuronal cell bodies of the sensory nerves that is shipped to the skin and joints causing increased levels of glutamate. A chronic increase in the production and release of glutamate can stimulate glutamate receptors on sensory nerves to produce painful sensations. For the current proposal, we hypothesize that elevated levels of glutamate cause 1exaggerated painful responses during chronic inflammation. In addition, preliminary data indicate that nerve growth factor (NGF) as a retrograde signal and zeta-crystallin:quinone oxidoreductase (ZC) as a stabilizer of glutaminase mRNA are important for this chronic alteration in glutamate metabolism. We postulate, therefore, that NGF and ZC are responsible for altering glutaminase levels in primary sensory neurons during chronic inflammation. The following specific aims are presented: 1. Our hypothesis predicts that inhibition of glutaminase will reduce nociceptive responses and elevated glutamate levels during chronic inflammation. A glutaminase inhibitor will be administered to sensory neurons during chronic inflammation. 2. Our hypothesis predicts that glutaminase production in sensory neurons during chronic inflammation is regulated by ZC. A ZC inhibitor will be given to sensory neurons during the development of chronic inflammation. 3. Our hypothesis predicts that glutamate metabolism in sensory neurons can be modified by NGF. NGF administration to naive rats and NGF inhibition during chronic inflammation will be evaluated. Behavioral tests will determine responses to pressure and temperature. Biochemical & immunohistochemical analyses will evaluate alterations in glutamate and GT enzyme levels in the sensory cell bodies and sensory nerves. Results from these studies will give insight into the role of peripheral glutamate on nociceptive responses during inflammatory chronic pain. These results may be beneficial in the development of novel therapies for patients with intractable pain by addressing the regulation of glutamate in peripheral tissues. ? ?
