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シンポジウム Neruochemical aspects of pain and its therapies. 2S7-1 Involvement of TRPV1 activation in pain and itch sensation Shibasaki Koji Dep Mol Cellular Neurobiology, Gunma Univ Grad Sch Medicine The capsaicin receptor, transient receptor potential vanilloid 1（TRPV1）, acts as a polymodal detector of pain-producing chemical and physical stimuli in sensory neurons. Hyperglycemia and hypoxia are two main phenomena in diabetes associated with several complications. Although many studies on streptozotocin-induced diabetic rats indicate that early diabetic neuropathy is associated with potentiation of TRPV1 activity in dorsal root ganglion neurons, its underlying mechanism and distinctive roles of hyperglycemia and hypoxia have not been completely clarified. In this symposium, we introduce that artificial hypoxic and high glucose conditions in vitro potentiate the TRPV1 activity without affecting TRPV1 expression in both native rat sensory neurons and HEK293 cells expressing rat or human TRPV1. Surprisingly, hypoxia was found to be a more effective determinant than high glucose, and hypoxia-inducible factor-1 alpha（HIF-1α）seemed to be involved. In addition, high glucose enhanced TRPV1 sensitization only when high glucose existed together with hypoxia. The potentiation of TRPV1 was caused by its phosphorylation of the serine residues, and translocation of protein kinase C（PKC）ε was clearly observed in the cells exposed to the hypoxic conditions in both cell types, which was inhibited by 2-methoxyestradiol, a HIF-1α inhibitor. These data suggest that hypoxia is a new sensitization mechanism for TRPV1, which might be relevant to diabetes-related complications, and also for other diseases that are associated with acute hypoxia. In addition to the effect of TRPV1 on the pain sensation in diabetes, we also introduce the involvement of TRPV1 on itch sensation through its activation by chemokines. 2S7-2 Chronic nociceptive stimuli induce “cell memory due to pain” with epigenetic modification Kuzumaki Naoko1，Narita Michiko1，Igarashi Katsuhide2，Narita Minoru1,2 1Dept. Pharmacol., Hoshi Univ. Sch. Pharm. Pharmaceut. Sci.，2Life Science Tokyo advanced Recerch Center（L-StaR） Neuropathic and inflammatory pain promote a large number of persisting adaptations at the cellular and molecular level, allowing even transient tissue or nerve damage to elicit changes in cells that contribute to the development of chronic pain and associated symptoms. There is evidence that injury-induced changes in chromatin structure drive stable changes in gene expression and neural function, which may cause several symptoms, including allodynia, hyperalgesia, anxiety, and depression. We have shown that a robust increase in MCP-3 protein, which lasts for up to 2 weeks after surgery, in the dorsal horn of the spinal cord of mice with sciatic nerve ligation is seen mostly in astrocytes, but not microglia or neurons. This increase in MCP-3 gene transcription was accompanied by the decreased trimethylation of histone H3 at lysine27（H3K27me3）at the MCP-3 promoter. The increased MCP-3 expression associated with its epigenetic modification observed in the spinal cord was almost abolished in interleukin-6（IL-6）knockout mice with sciatic nerve ligation. It has been reported that a Jumonji domein containing 3（JMJD3）function as transcriptional activators that demethylate H3K27me3. Therefore we performed ChIP assays with antibodies against JMJD3 at the promoter region of MCP-3. As a result, sciatic nerve ligation significantly increased the induction of jmjd3 at MCP-3 promoter. These findings suggest that increased MCP-3 expression associated with IL-6-dependent epigenetic modification at the MCP-3 promoter after nerve injury, mostly in spinal astrocytes, may serve to facilitate astrocyte-microglia-neuron interaction in the spinal cord. In this symposium, we will also discuss the importance of epigenetic changes in another molecular targets for chronic pain. 2S7-3 Neurotransmitters Modulating Pain Inhibitory Pathways Suto Takashi Department of Anesthesiology, Gunma University Graduate School of Medicine The spinal dorsal horn is the powerful target of regulation of pain signaling by local and supraspinal mechanisms. Descending control of spinal nociception originate from many brain regions and plays critical roles in determining the experience of both acute and chronic pain. Most clinically available analgesic drugs for acute and chronic pain, like opiates and α2 adrenenoceptor agonists, change the descending pain controlling pathways. In this presentation, I focus on the noradrenaline/serotonin systems, which originate from locus coeruleus（LC）and rostalventrolateral medulla（RVM）respectively, and will discuss about their roles in pain modulation and modulation of other brain functions. In chronic neuropathic pain model, plastic change of the descending pathways of noradrenaline/serotonin are related to the pain processing including the effects of endogenous analgesia and the effects of analgesic drugs. 2S7-4 Microglial transcription factors and neuropathic pain Tsuda Makoto1，Masuda Takahiro1，Tozaki-Saitoh Hidetoshi1，Inoue Kazuhide2 1Dept. Life Innov., Grad. Sch. Pharmaceut. Sci., Kyushu Univ.，2Dept. Mol. Syst. Pharmacol., Grad. Sch. Pharmaceut. Sci., Kyushu Univ. In contrast to physiological pain, pathological pain is not dependent on the presence of tissue-damaging stimuli. One type of pathological pain-neuropathic pain-is often a consequence of nerve injury or of diseases. Neuropathic pain can be agonizing, can persist over long periods, and is often resistant to known painkillers. A growing body of evidence indicates that many pathological processes within the CNS are mediated by complex interactions between neurons and glial cells. In the case of painful peripheral neuropathy, spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. Results of our laboratory have demonstrated that the transcription factor interferon regulatory factor-8（IRF8）is upregulated in spinal microglia after peripheral nerve injury（PNI）and regulates expression of genes crucial for converting the cells to reactive ones. Furthermore, we recently identify IRF5 as a target of IRF8 and as being required for upregulation of P2X4 receptors（P2X4Rs；ATP-gated channels essential for producing neuropathic pain）. PNI increased expression of IRF5 in spinal microglia in a cell type-specific manner. The upregulation of IRF5 expression was abolished in IRF8-deficient mice. IRF5 induced expression of P2X4R by directly binding to the promoter region of the P2rx4 gene. Mice lacking Irf5 did not upregulate spinal P2X4R after PNI, and also exhibited substantial resistance to pain hypersensitivity. Thus, an IRF8-IRF5 transcriptional axis contributes to shifting spinal microglia toward a P2X4R-expressing reactive state after PNI. These results may provide a new target for treating neuropathic pain.