In a new mouse model for generalized pain syndrome, including fibromyalgia, which used intermittent cold stress (ICS), bilateral allodynia in the hindpaw was observed that lasted more than 12 days; thermal hyperalgesia lasted 15 days. During constant cold stress (CCS), mice showed only a transient allodynia. A female prevalence in ICS-induced allodynia was observed in gonadectomized but not in gonad intact mice. Systemic gabapentin showed complete anti-allodynic effects in the ICS model at the one-tenth dose for injury-induced neuropathic pain model, and central gabapentin showed long-lasting analgesia for 4 days in ICS, but not the injury model. These results suggest that the ICS model is useful for the study of generalized pain syndrome. FindingsFibromyalgia syndrome (FMS) is a highly prevalent (~2% of all citizens) chronic pain disease, which has unique characteristics including generalized or widespread allodynia and a female preponderance [1][2][3][4]. According to recent reports, physical and psychological stressors are believed to trigger FMS [5][6][7][8][9]. Although there are several trials underway to make existing medicines available for FMS treatment, attempts to develop a compound specific for FMS are yet to be performed. One reason is the lack of established experimental animal models for FMS, although several models have been proposed [10][11][12][13]. Here, we report a pharmacological study using a new generalized chronic pain or FMS model, using intermittent cold stress.We improved the mouse model for dysautonomia, also referred to as the specific alternation of rhythm in temperature (SART) model [14,15]. To develop the stress model of mice with reproducible and long-lasting allodynia and hyperalgesia, we evaluated several different stress paradigms. With regard to a temperature of the cold room, the temperature of 4 ± 2°C gave rise to long-lasting allodynia. At the temperature over 6°C, long-lasting and stable allodynia was not observed. For quick changes in temperature between 4 and 24°C, we used a meshed stainless steel floor in each cage, and transferred mice individually, leaving the stainless floor in the cold room. Trials with different numbers of mice in the same cage, ranging from one to eight mice, revealed that the number of mice in the same cage should be two. Although frequent temperature change is expected to be more stressful, an interval of more than 30 min was estimated to be minimal for the switch between 4 and 24°C. To maintain healthy conditions in the cold room, food pellets and gelatin as the water supply were placed on the floor of the cage in the cold room, owing to the lowered spontaneous activities of mice in such conditions. For stable nociception, an adaptation period of at least 1 h before the nociception tests was necessary.

No abstract

BackgroundFibromyalgia (FM) is characterized by chronic widespread pain, which is often refractory to conventional painkillers. Numerous clinical studies have demonstrated that antidepressants are effective in treating FM pain. We previously established a mouse model of FM-like pain, induced by intermittent cold stress (ICS).ResultsIn this study, we find that ICS exposure causes a transient increase in plasma corticosterone concentration, but not in anxiety or depression-like behaviors. A single intrathecal injection of an antidepressant, such as milnacipran, amitriptyline, mianserin or paroxetine, had an acute analgesic effect on ICS-induced thermal hyperalgesia at post-stress day 1 in a dose-dependent manner. In addition, repeated daily antidepressant treatments during post-stress days 1-5 gradually reversed the reduction in thermal pain threshold, and this recovery was maintained for at least 7 days after the final treatment. In addition, relief from mechanical allodynia, induced by ICS exposure, was also observed at day 9 after the cessation of antidepressant treatment. In contrast, the intravenous administration of these antidepressants at conventional doses failed to provide relief.ConclusionsThese results suggest that the repetitive intrathecal administration of antidepressants permanently cures ICS-induced FM pain in mice.

The intermittent cold stress‐induced generalized pain response mimics the pathophysiological and pharmacotherapeutic features reported for fibromyalgia patients, including the presence of chronic generalized pain and female dominance. In addition, the intermittent cold stress‐induced generalized pain is abolished in lysophosphatidic acid receptor type‐1 knockout mice, as reported in many cases of neuropathic pain models. This study aimed to identify the brain loci involved in the intermittent cold stress generalized pain response and test their dependence on the lysophosphatidic acid receptor type‐1. Positron emission tomography analyses using 2‐deoxy‐2‐[18F]fluoro‐d‐glucose in the presence of a pain stimulus showed that intermittent cold stress causes a significant increase in uptake in the ipsilateral regions, including the salience networking‐related anterior cingulate cortex and insular cortex and the cognition‐related hippocampus. A significant decrease was observed in the default mode network‐related posterior cingulate cortex. Almost these intermittent cold stress‐induced changes were abolished in lysophosphatidic acid receptor type‐1 knockout mice. There results suggest that the intermittent cold stress‐induced generalized pain response is mediated by the lysophosphatidic acid receptor type‐1 in specific brain loci related to salience networking and cognition, which may lead to further developments in the treatment of fibromyalgia.

After the breakthrough in the treatment of rheumatoid arthritis and numerous related disorders with biological therapies targeting TNFa at the Kennedy Institute in London Millions of patients have tremendously benefitted. However, we cannot cure these diseases yet and have to search for additional therapeutic targets. Since it was shown that synovial fibroblasts (SF) are not only effector cells responding to inflammatory stimuli, but appear endogenously activated and potentially involved into spreading the disease [1], we searched for the epigenetic modifications leading to the activated phenotype of these cells. Epigenetics in its scientific definition "is the study of all heritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA", but might be considered in simpler terms as the regulation of gene expression. Epigenetic modifications include: Acetylation, Methylation, Phosphorylation, Sumoylation, miRs or microRNAs. Our laboratory is studying these processes and we have found that RASF reside in a hyperacetylated synovial tissue and appear hypomethylated [2]. Hypomethylation leads to the activated phenotype of RASF which is characterized by the production of matrix-degrading enzymes and of potent chemokines induced by Toll-like receptor signalling. Current strategies are designed to methylate these cells to deactivate and "normalise" them again. miRs are about 20 nucleotide long smallRNAs acting to destroy specific mRNA. In the race to identify specific miRs as novel targets we have identified for example, that interleukin-6 modulates the expression of the Bone Morphogenic Protein Receptor Type II through a novel STAT3microRNA cluster 17/92 pathway, which helps to explain the loss of the BMPR2 in the vascular cells in pulmonary hypertension [3]. Moreover, miR-203 is regulating the production of IL-6 [4]. Most interestingly, epigenetic therapy is also on the horizon [5]. References 1. Lefèvre S, et al: Synovial fibroblasts spread rheumatoid arthritis to unaffected joints.