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Role of dorsal root ganglion glutaminase in nociception - A novel therapeutic target for inflammatory pain

Hoffman, Ernest Matthew
Abstract
Scope and Method of Study: The purpose of this study was to examine the distribution of the enzyme glutaminase in rat dorsal root ganglion and determine its potential as a target for analgesic development. The study used a combination of behavioral analysis and quantitative microscopy to investigate the distribution of glutaminase in the rat dorsal root ganglion, expression of glutaminase during inflammation, expression of glutaminase under conditions of nerve growth factor depletion, and effect of glutaminase inhibition on inflammation induced Fos expression in spinal cord.
Findings and Conclusions: Glutaminase was found to be distributed ubiquitously in rat dorsal root ganglion neurons. Past discrepancies on its distribution were attributed to tissue fixation methods, and optimization of tissue fixation proved useful in properly identifying distributions of other proteins in the dorsal root ganglion. Glutaminase expression in dorsal root ganglion neurons was increased after four days of hind paw inflammation and remained elevated after eight days in small diameter neurons. Autoimmunization with nerve growth factor was effective at depleting nerve growth factor levels and causing hypoalgesia as had been reported previously. Deprivation of nerve growth factor did not alter basal expression of glutaminase in dorsal root ganglion neurons, but it did decrease expression the voltage-gated sodium channel Nav1.8 in small isolectin B4 negative neurons. Lastly, peripheral inhibition of glutaminase during carrageenan induced inflammation decreased spinal cord Fos expression, which is typically an indicator of nociceptive activity at the spinal level. Clarification of glutaminase distribution, understanding its basal regulation and in response to inflammation, and demonstrating the effectiveness of its inhibition at decreasing activity in pain pathways gave support for nomination of glutaminase as a novel therapeutic target for inflammatory pain.
Date
2009-05