BACKGROUND AND PURPOSEHypoesthesia is a clinical feature of neuropathic pain. The feature is partly explained by the evidence of epigenetic repression of Nav1.8 sodium channel in the dorsal root ganglion (DRG). EXPERIMENTAL APPROACHWe investigated the possibility of trichostatin A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to reverse the unique C-fibre sensitivity observed following partial ligation of sciatic nerve in mice. KEY RESULTSNerve injury-induced down-regulation of DRG Nav1.8 sodium channel and C-fibre-related hypoesthesia were reversed by TSA, VPA and SAHA treatments, which inhibit histone deacetylase (HDAC), and increase histone acetylation at the regulatory sequence of Nav1.8. CONCLUSIONS AND IMPLICATIONSTaken together, these studies provide the evidence that hypoesthesia and underlying down-regulation of Nav1.8, negative symptoms observed in nerve injury-induced neuropathic pain models are regulated by an epigenetic chromatin remodelling through HDAC-related machineries.

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.

Neuropathic pain is often insensitive to morphine. Our previous study has demonstrated that neuron-restrictive silencer factor represses mu opioid receptor (MOP) gene expression in the dorsal root ganglion (DRG) via histone hypoacetylation-mediated mechanisms after peripheral nerve injury, thereby causing loss of peripheral morphine analgesia. Here, we showed that histone deacetylase (HDAC) inhibitors, such as trichostatin A and valproic acid, restored peripheral and systemic morphine analgesia in neuropathic pain. Also, these agents blocked nerve injury-induced MOP down-regulation in the DRG. These results suggest that HDAC inhibitors could serve as adjuvant analgesics to morphine for the management of neuropathic pain.

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.

In vivo microdialysis is a technology to measure the concentration of a target substance in extracellular fluid at a localized site by collecting the substance through a dialysis membrane. In the brain, the dialysate enables us to assess real-time changes in neurotransmitters. Therefore, the technique is a useful method for the pharmacological action of central nervous system compounds. In order to fully support researchers, we would like to present an example of the antidepressant evaluation systems using the dialysate from various brain regions in rodents. 【Methods & Results】 A microdialysis probe was inserted into each of the hippocampus or the medial prefrontal cortex (mPFC) in C57BL/6J mice. After 2hour of pre-perfusion, the dialysate was collected at 20-minute intervals at a flow rate of 1µL/min. Then, mice were treated with intraperitoneal injection of R-fluoxetine, a selective serotonin reuptake inhibitor for the treatment of depression, and the dialysate was recollected. The next day, dopamine and serotonin levels were measured by HPLC-ECD. As a result of the study, serotonin release was significantly increased in the hippocampus compared to pre-administration. On the other hand, dopamine release was significantly increased in mPFC compared to pre-administration. 【Conclusions】 In this study, we confirmed the effects of a single antidepressant administration on brain monoamines in wild-type mice. We will continue to introduce a wide range of technologies and evaluation systems to provide value-added preclinical testing services.