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Stress has a strong influence on pain perception and may result in either increased or decreased sensitivity depending on the challenging conditions. Accordingly, stress appears to play a central role in many functional somatoform disorders such as fibromyalgia.
To create a long lasting stressful situation, male Wistar rats were exposed to a single restraint stress for 1 h only once or over periods of either one or two weeks.
The effect on nociception was evaluated using the Randall-Selitto- and the tail-flick-test. After two weeks the animals exhibited a significant hyperalgesia in both tests. Due to the higher effect size and better comparability for pressure pain of tender points in human fibromyalgia syndrome further nociceptive testing was restricted to the Randall-Selitto-test. Additional analysis showed that rats with increased pain sensitivity also displayed elevated plasma levels of corticosterone with an accompanied enlargement of adrenal glands indicating a dysregulation of the hypothalamic-pituitary-adrenal axis, which play a key role in the stress response.
In order to test for a possible correlation of HPA-axis dysregulation and hyperalgesia a persistent increase in plasma corticosterone was generated in Wistar rats by the administration of different concentrations of corticosterone via drinking water for two weeks. Additionally the measurement of plasma ACTH and histological examination of the adrenal cortex, which represents the site of corticosterone synthesis, were preformed. Similar to the restraint stressed rats animals consuming different concentrations of corticosterone in drinking water exhibited also a significant mechanical hyperalgesia, indicating a dose-dependency to the amount of corticosterone in drinking water.
These animals showed as well dose-dependent a concurrent reduction of the adrenal zona fasciculata and reduced ACTH plasma levels. On the other hand, the restraint animals exhibited an enlarged adrenal cortex and increased ACTH plasma levels. Thus it is the concluded that within a dysregulated HPA-axis, especially the persistently elevated plasma levels of corticosterone are associated with hyperalgesia. For further elucidation of this relationship studies were carried out on glucocorticoid receptors. For this purpose, from restrained and corticosterone drinking animals spleen lymphocytes were obtained, which were used for determination of responsiveness and density of glucocorticoid receptors.
The lymphocytes of these animals showed a reduced sensitivity of glucocorticoid receptors with an accompanied increase of receptor density, which is assumed to be an attempted decompensation mechanism. Furthermore, it supposed that the observed glucocorticoid receptor alterations may contribute to increased pain sensitivity, since a number of nociception-modulating neurotransmitters is affected by this receptor. In order to validate the hyperalgesia models and to obtain additional information on the underlying mechanisms, different drugs which are used in the therapy of functional somatoform pain disorders were tested by oral administration. In addition to the serotonin–norepinephrine reuptake inhibitor Milnacipran, the opioide levomethadone was found to be active in both models while the NMDA-antagonist ketamine abolished mainly the restraint stress-induced hyperalgesia. In contrast, no effect was observed for the COX-inhibitor diclofenac in both stress- and corticosterone-induced hyperalgesia.
The results indicate that a dysregulated corticosterone secretion leads in both hyperalgesia models to glucocorticoid receptor alterations, resulting in an increased pain perception due the influence on nociception-modulating neurotransmitters. Finally, both models seem to possess predictive validity as inhibition of hyperalgesia could be demonstrated for drugs used therapeutically to treat of functional somatoform pain disorders. Under animal welfare aspects the corticosterone-induced hyperalgesia model is a new animal friendly experimental method for mimicking stress effects on nociception.