Glucocorticoid-mediated enhancement of glutamatergic transmission may outweigh anti-inflammatory effects under conditions of neuropathic pain

• Published in: PloS one Vol. 9; no. 3; p. e91393
• Main Authors: Le Coz, Glenn-Marie, Anton, Fernand, Hanesch, Ulrike
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.03.2014; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Biology; Body weight; Body Weight - drug effects; Chronic pain; Corticosterone; Cytokines; Cytokines - genetics; Cytokines - metabolism; Dexamethasone; Disease Models, Animal; Gene Expression; Glucocorticoids; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; Glutamate; Glutamatergic transmission; Glutamic Acid - metabolism; Glutamic acid receptors (ionotropic); Glutamic acid receptors (metabotropic); Hypothalamus; Inflammation; Kinases; Laboratories; Male; Mifepristone - administration & dosage; Mifepristone - pharmacology; N-Methyl-D-aspartic acid receptors; Neuralgia; Neuralgia - drug therapy; Neuralgia - etiology; Neuralgia - metabolism; Neuropathy; Oral contraceptives; Pain; Pain sensitivity; Pain Threshold - drug effects; Peripheral Nerve Injuries - complications; Pituitary; Rats; Receptors; Receptors, Glucocorticoid - agonists; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - metabolism; RNA; Rodents; Sensitivity; Sensitivity enhancement; Steroids (Organic compounds); Surgery; Synaptic Transmission - drug effects; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0091393

At the clinical level comorbidity between chronic pain and dysfunctional hypothalamus-pituitary-adrenal (HPA) axis is well established. We aimed to identify causal relationships in a model of neuropathic pain (chronic constriction injury, CCI) by studying the effects of glucocorticoid receptor agonist (dexamethasone) and antagonist (RU-486) administration on pain behavior and spinal biochemical mediators. Daily injections were performed in Sprague Dawley rats. Weight, plasma corticosterone levels and mechanical pain thresholds were assessed before and during 21 days post-CCI. At days four and 21 we investigated the mRNA expression of spinal mediators. In the dexamethasone-injected group, we observed a diminution of body weight and plasma corticosterone levels during the 21 days post surgery period and a more pronounced pain sensitivity until day 7 post-CCI. This enhanced pain sensitivity in the early period following nerve injury was accompanied by a transient increase of the glutamate receptors mGluR5 and NMDA at day 4. However, at this time point we did not observe any effect of the agonist/antagonist injections on the mRNA expression of pro-inflammatory cytokines. The RU-486-injected rats showed a slight mechanical hypoalgesia until 7 days post-CCI, but without any significant correlation with the expression of the measured markers. Our results indicate that glucocorticoid-related modulations of neuropathic pain processing may rather depend on a modification of glutamatergic transmission than on a change in pro-inflammatory cytokine expression.