2021/12/04 更新

写真a

ウチダ ヒトシ
内田 仁司
UCHIDA Hitoshi
所属
脳研究所 助教
職名
助教
外部リンク

学位

  • 博士(薬学) ( 2009年3月   長崎大学 )

研究キーワード

  • イメージング

  • 一次知覚神経

  • エピジェネティクス

  • RNA編集

  • 痛み

  • 痒み

  • 組織透明化

研究分野

  • ライフサイエンス / 神経科学一般

経歴

  • 新潟大学   脳研究所 基礎神経科学部門 細胞神経生物学   助教

    2015年3月 - 現在

所属学協会

委員歴

  • 日本薬理学会   学術評議員  

    2015年4月 - 現在   

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    団体区分:学協会

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論文

  • Allodynia by Splenocytes From Mice With Acid-Induced Fibromyalgia-Like Generalized Pain and Its Sexual Dimorphic Regulation by Brain Microglia. 査読 国際誌

    Hiroshi Ueda, Naoki Dozono, Keigo Tanaka, Shuji Kaneko, Hiroyuki Neyama, Hitoshi Uchida

    Frontiers in neuroscience   14   600166 - 600166   2020年12月

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    担当区分:最終著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Fibromyalgia (FM), a disease of unknown etiology characterized by chronic generalized pain, is partly recapitulated in an animal model induced by repeated acid saline injections into the gastrocnemius muscle. Here, we attempted to investigate the sex difference in pain hypersensitivity (mechanical allodynia and hypersensitivity to electrical stimulation) in the repeated acid saline-induced FM-like generalized pain (AcGP) model. The first unilateral acid injection into gastrocnemius muscle at day 0/D0 and second injection at D5 (post day 0, P0) induced transient and long-lasting mechanical allodynia, respectively, on both sides of male and female mice. The pretreatment with gonadectomy did not affect the first injection-induced allodynia in both sexes, but gradually reversed the second injection-induced allodynia in male but not female mice. Moreover, the AcGP in male mice was abolished by intracerebroventricular minocycline treatments during D4-P4 or P5-P11, but not by early treatments during D0-D5 in male but not female mice, suggesting that brain microglia are required for AcGP in late-onset and sex-dependent manners. We also found that the intravenous treatments of splenocytes derived from male but not female mice treated with AcGP caused allodynia in naive mice. In addition, the purified CD4+ T cells derived from splenocytes of acid-treated male mice retained the ability to cause allodynia in naive mice. These findings suggest that FM-like AcGP has multiple sexual dimorphic mechanisms.

    DOI: 10.3389/fnins.2020.600166

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  • Mirtazapine, an α2 antagonist-type antidepressant reverses pain and lack of morphine analgesia in fibromyalgia-like mouse models. 査読 国際誌

    Hiroyuki Neyama, Naoki Dozono, Hitoshi Uchida, Hiroshi Ueda

    The Journal of pharmacology and experimental therapeutics   375 ( 1 )   1 - 9   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Treatment for fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain, but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)-induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine (Mir), which is presumed to disinhibit 5-HT release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic α2, postsynaptic 5-HT2 and 5-HT3 receptors, completely reversed the chronic pain for more than 4-5 days after the cessation of treatments. The repeated Mir-treatments also recovered the morphine analgesia after the return of nociceptive threshold to the normal level. The microinjection of siRNA adrenergic α2a receptor (ADRA2A) into the habenula, which showed a selective upregulation of α2 receptor gene expression after ICS, reversed the hyperalgesia, but did not recover the morphine analgesia. However, both reversal of hyperalgesia and recovery of morphine analgesia were observed when siRNA ADRA2A was administered intracebroventricularly. As the habenular is reported to be involved in the emotion/reward-related pain and hypoalgesia, these results suggest that Mir could attenuate pain and/or augment hypoalgesia by blocking the habenular α2 receptor after ICS. The recovery of morphine analgesia in the ICS model, on the other hand, seems to be mediated through a blockade of α2 receptor in unidentified brain regions. SIGNIFICANCE STATEMENT: This study reports possible mechanisms underlying the complete reversal of hyperalgesia and recovery of morphine analgesia by mirtazapine, a unique antidepressant with adrenergic α2 and serotonergic receptor antagonist properties, in a type of intermittently repeated stress (ICS)-induced fibromyalgia-like pain model. Habenula, a brain region which is related to the control of emotional pain, was found to play key roles in the anti-hyperalgesia, while other brain regions appeared to be involved in the recovery of morphine analgesia in the ICS-model.

    DOI: 10.1124/jpet.120.265942

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  • GRP receptor and AMPA receptor cooperatively regulate itch-responsive neurons in the spinal dorsal horn. 査読 国際誌

    Norikazu Kiguchi, Daisuke Uta, Huiping Ding, Hitoshi Uchida, Fumihiro Saika, Shinsuke Matsuzaki, Yohji Fukazawa, Manabu Abe, Kenji Sakimura, Mei-Chuan Ko, Shiroh Kishioka

    Neuropharmacology   170   108025 - 108025   2020年6月

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    記述言語:英語  

    Gastrin-releasing peptide (GRP) receptor-expressing (GRPR)+ neurons have a central role in the spinal transmission of itch. Because their fundamental regulatory mechanisms are not yet understood, it is important to determine how such neurons are excited and integrate itch sensations. In this study, we investigated the mechanisms for the activation of itch-responsive GRPR+ neurons in the spinal dorsal horn (SDH). GRPR+ neurons expressed the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) containing the GluR2 subunit. In mice, peripherally elicited histaminergic and non-histaminergic itch was prevented by intrathecal (i.t.) administration of the AMPAR antagonist NBQX, which was consistent with the fact that firing of GRPR+ neurons in SDH under histaminergic and non-histaminergic itch was completely blocked by NBQX, but not by the GRPR antagonist RC-3095. Because GRP+ neurons in SDH contain glutamate, we investigated the role of GRP+ (GRP+/Glu+) neurons in regulating itch. Chemogenetic inhibition of GRP+ neurons suppressed both histaminergic and non-histaminergic itch without affecting the mechanical pain threshold. In nonhuman primates, i.t. administration of NBQX also attenuated peripherally elicited itch without affecting the thermal pain threshold. In a mouse model of diphenylcyclopropenone (DCP)-induced contact dermatitis, GRP, GRPR, and AMPAR subunits were upregulated in SDH. DCP-induced itch was prevented by either silencing GRP+ neurons or ablation of GRPR+ neurons. Altogether, these findings demonstrate that GRP and glutamate cooperatively regulate GRPR+ AMPAR+ neurons in SDH, mediating itch sensation. GRP-GRPR and the glutamate-AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates.

    DOI: 10.1016/j.neuropharm.2020.108025

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  • Two isoforms of cyclic GMP-dependent kinase-I exhibit distinct expression patterns in the adult mouse dorsal root ganglion. 査読

    Uchida H, Matsumura S, Katano T, Watanabe M, Schlossmann J, Ito S

    Molecular pain   14   1744806918796409   2018年1月

  • RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury 査読

    Hitoshi Uchida, Shinji Matsumura, Shunpei Okada, Tsutomu Suzuki, Toshiaki Minami, Seiji Ito

    FASEB JOURNAL   31 ( 5 )   1847 - 1855   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:FEDERATION AMER SOC EXP BIOL  

    Transcriptional and post-translational regulations are important in peripheral nerve injury-induced neuropathic pain, but little is known about the role of post-transcriptional modification. Our objective was to determine the possible effect of adenosine deaminase acting on RNA (ADAR) enzymes, which catalyze post-transcriptional RNA editing, in tactile allodynia, a hallmark of neuropathic pain. Seven days after L5 spinal nerve transection (SNT) in adultmice, we found an increase in ADAR2 expression and a decrease in ADAR3 expression in the injured, but not in the uninjured, dorsal root ganglions (DRGs). These changes were accompanied by elevated levels of editing at the D site of the serotonin (5-hydroxytryptamine) 2C receptor (5-HT2CR), at the I/V site of coatomer protein complex subunit alpha(COPA), and at the R/G site of AMPA receptor subunit GluA2 in the injured DRG. Compared to Adar2(+/+)/Gria2(R/R) littermate controls, Adar2(+/+)/Gria2(R/R) mice completely lacked the increased editing of 5-HT2CR, COPA, and GluA2 transcripts in the injured DRG and showed attenuated tactile allodynia after SNT. Furthermore, the antidepressant fluoxetine inhibited neuropathic allodynia after injury and reduced the COPAI/V site editing in the injured DRG. These findings suggest that ADAR2 is a mediator of injury-induced tactile allodynia and thus a potential therapeutic target for the treatment of neuropathic pain.-Uchida, H., Matsumura, S., Okada, S., Suzuki, T., Minami, T., Ito, S. RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury.

    DOI: 10.1096/fj.201600950R

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  • Phosphorylation of NMDA receptor GluN2B subunit at Tyr1472 is important for trigeminal processing of itch 査読

    Akitoshi Inoue, Hitoshi Uchida, Takanobu Nakazawa, Tadashi Yamamoto, Seiji Ito

    EUROPEAN JOURNAL OF NEUROSCIENCE   44 ( 7 )   2474 - 2482   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Itch and pain are intimately related and may share similar peripheral and central mechanisms and pathways. However, it has been believed that synaptic glutamate release from a group of peripheral nociceptors is required to sense pain and suppress itch. Although we previously demonstrated that phosphorylation of GluN2B subunits of the NMDA receptor at Tyr1472 is important for central sensitization in a neuropathic pain model of mice with a knock-in mutation of the Tyr1472 site to phenylalanine of GluN2B (Y1472F-KI), the role of NMDA receptors in itch transmission remains unknown. Here, we demonstrated that the scratching behaviors elicited by various pruritogens applied to the cheek and c-fos expression in the region innervated by the trigeminal nerve were markedly attenuated in the Y1472F-KI mice. The c-fos immunoreactivity was co-localized with the receptor of gastrin-releasing peptide (GRP). Scratching behaviors evoked by chloroquine were inhibited by the NMDA receptor antagonists D-AP5 and CP101,606 and by the Src kinase inhibitor PP2. Direct activation of the trigeminal region by intracisternal administration of NMDA and GRP induced robust scratching behaviors, both of which were reduced by the GRP receptor antagonist RC-3095. Taken together, the data obtained in this present study are the first to demonstrate that phosphorylation of GluN2B subunit at Tyr1472 is important for trigeminal transmission of itch and suggest that the NMDA receptor activation occurs upstream of the GRP-GRP receptor pathway.

    DOI: 10.1111/ejn.13337

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  • Differential regulation of expression of RNA-editing enzymes, ADAR1 and ADAR2, by 5-aza-2 '-deoxycytidine and trichostatin A in human neuronal SH-SY5Y cells 査読

    Hitoshi Uchida, Seiji Ito

    NEUROREPORT   26 ( 18 )   1089 - 1094   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Adenosine deaminase acting on RNA (ADAR) enzymes, ADAR1 and ADAR2, mediates adenosine-to-inosine RNA editing, and their mRNA expressions are altered during developmental, physiological, and pathophysiological processes in the nervous system. The present study attempted to investigate the involvement of epigenetic modifying enzymes, such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC), in the regulation of ADAR1 and ADAR2 mRNA expressions in neuronal cells. Using human neuronal SH-SY5Y cells, we found that the DNMT inhibitor 5-aza-2-deoxycytidine led to an increase in ADAR2, but not ADAR1, mRNA expression in a concentration-dependent and time-dependent manner. However, treatment with HDAC inhibitor trichostatin A elicited an increase in ADAR2 mRNA expression and a decrease in ADAR1 mRNA expression, and these changes were blocked by actinomycin D, a transcription inhibitor. Taken together, these findings suggest that ADAR1 and ADAR2 expressions are subject to different regulations by DNMT and HDAC enzymes in neuronal SH-SY5Y cells.

    DOI: 10.1097/WNR.0000000000000474

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  • Histone deacetylase inhibitors relieve morphine resistance in neuropathic pain after peripheral nerve injury 査読

    Hitoshi Uchida, Yosuke Matsushita, Kohei Araki, Takehiro Mukae, Hiroshi Ueda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   128 ( 4 )   208 - 211   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

    Neuropathic pain is often insensitive to morphine. Our previous study has demonstrated that neuronrestrictive 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. (c) 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

    DOI: 10.1016/j.jphs.2015.07.040

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  • Donepezil Reverses Intermittent Stress-Induced Generalized Chronic Pain Syndrome in Mice 査読

    Takehiro Mukae, Hitoshi Uchida, Hiroshi Ueda

    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS   353 ( 3 )   471 - 479   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

    Treatment of fibromyalgia is an unmet medical need. To develop novel therapies for the treatment of fibromyalgia, we explored pain therapeutic actions of existing pharmaceuticals, which inhibit the somatic symptoms frequently observed in fibromyalgia patients. This study first examined the therapeutic actions of pilocarpine, which inhibits dry-eye and dry-mouth symptoms, using an experimental fibromyalgia-like chronic pain model produced by intermittent cold stress (ICS) in mice. A single intraperitoneal and intracerebroventricular, but not intrathecal, pilocarpine administration attenuated ICS-induced thermal hyperalgesia and mechanical allodynia, and this action was abolished by muscarinic antagonist pirenzepine (i.c.v.). Treatment with 1-10 mg/kg donepezil (i.p.), which can easily penetrate into the brain, also showed similar therapeutic effects. Importantly, we found that both pilocarpine and donepezil produced antihyperalgesic effects via supraspinal action. Furthermore, repeated donepezil treatments completely cured the ICS-induced hyperalgesia and allodynia even after the cessation of drug treatments. Acute and chronic treatments of these cholinomimetics had no effects on the nociceptive threshold in control animals. By contrast, the lack of morphine (i.c.v.) analgesia initially observed in the ICS model remained in ICS model mice treated with long-term donepezil. Collectively, these findings suggest that stimulation of the muscarinic cholinergic system effectively inhibits some mechanisms underlying chronic pain in the ICS model, but does not inhibit the lack of descending pain-inhibitory mechanisms, which are driven by central morphine.

    DOI: 10.1124/jpet.114.222414

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  • Epigenetic Modification in Neuropathic Pain 査読

    Hiroshi Ueda, Hitoshi Uchida

    CURRENT PHARMACEUTICAL DESIGN   21 ( 7 )   849 - 867   2015年

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    記述言語:英語   出版者・発行元:BENTHAM SCIENCE PUBL LTD  

    Neuropathic pain is characterized by complicated combination of positive (e.g., hyperalgesia and allodynia) and negative (e. g., hypoesthesia and hypoalgesia) symptoms, and is often refractory to conventional pharmacological agents, including morphine. Although the molecular mechanisms for positive symptoms are extensively studied, those for negative symptoms are poorly understood. There is convincing evidence that altered gene expression within peripheral and central nervous systems is a key mechanism for neuropathic pain; however, its transcriptional mechanisms are poorly understood. Epigenetic modifications, such as DNA methylation and histone modifications (e.g., acetylation, methylation, and phosphorylation), are known to cause stable gene expression via chromatin remodeling. These mechanisms have a role not only in the determination of developmental cell fates, but also in the physiological and pathological processes in nervous system. Moreover, epigenetic therapies using epigenetic modifying compounds are progressively advanced in the treatments of diverse diseases, including cancer and neurological diseases. Importantly, there is emerging evidence that a variety of genes undergo epigenetic regulation via DNA methylation and histone modifications within peripheral and central nervous systems, thereby contributing to the alterations in both pain sensitivity and pharmacological efficacy in neuropathic pain. In this review, we will highlight the epigenetic gene regulation underlying neuropathic pain, especially focusing on the negative symptoms. Moreover, we will discuss whether epigenetic mechanisms can serve as a potential target to treat neuropathic pain.

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  • Lysophosphatidic acid and its receptors LPA(1) and LPA(3) mediate paclitaxel-induced neuropathic pain in mice 査読

    Hitoshi Uchida, Jun Nagai, Hiroshi Ueda

    MOLECULAR PAIN   10   71   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Paclitaxel, which is widely used for the treatment of solid tumors, causes neuropathic pain via poorly understood mechanisms. Previously, we have demonstrated that lysophosphatidic acid (LPA) and its receptors (LPA(1) and LPA(3)) are required for the initiation of peripheral nerve injury induced neuropathic pain. The present study aimed to clarify whether LPA and its receptors could mediate paclitaxel-induced neuropathic pain.
    Results: Intraperitoneal administration of paclitaxel triggered a marked increase in production of LPA species (18:1-, 16:0-, and 18:0-LPA) in the spinal dorsal horn. Also we found significant activations of spinal cytosolic phospholipase A(2) and calcium independent phospholipase A2 after the paclitaxel treatment. The paclitaxel-induced LPA production was completely abolished not only by intrathecal pretreatment with neurokinin 1 (NK1) or N-methyl-(D)-aspartate (NMDA) receptor antagonist, but also in LPA(1) receptor deficient (Lpar1(-/-)) and LPA3 receptor deficient (Lpar3(-/-)) mice. In addition, the pharmacological blockade of NK1 or NMDA receptor prevented a reduction in the paw withdrawal threshold against mechanical stimulation after paclitaxel treatments. Importantly, the paclitaxel-induced mechanical allodynia was absent in Lparl(-/-) and Lpar3(-/-) mice.
    Conclusions: These results suggest that LPA(1) arid LPA(3) receptors mediated amplification of spinal LPA production is required for the development of paclitaxel-induced neuropathic pain.

    DOI: 10.1186/1744-8069-10-71

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  • Identification of nitrated tyrosine residues of protein kinase G-Iα by mass spectrometry. 査読

    Lu J, Yao I, Shimojo M, Katano T, Uchida H, Setou M, Ito S

    Analytical and bioanalytical chemistry   406 ( 5 )   1387 - 1396   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s00216-013-7535-4

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  • EPIGENETIC REGULATION OF BDNF EXPRESSION IN THE PRIMARY SENSORY NEURONS AFTER PERIPHERAL NERVE INJURY: IMPLICATIONS IN THE DEVELOPMENT OF NEUROPATHIC PAIN 査読

    H. Uchida, Y. Matsushita, H. Ueda

    NEUROSCIENCE   240   147 - 154   2013年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Brain-derived neurotrophic factor (BDNF) is known to be up-regulated in the dorsal root ganglion (DRG) after peripheral nerve injury, and to contribute to neuropathic pain. Here, we found that thermal hyperalgesia and mechanical allodynia at day 7 post-injury were inhibited only when anti-BDNF antibody was intrathecally administrated at day 2 post-injury. Consistent with behavioral results, Western blot analysis showed that the expression levels of BDNF protein in the spinal dorsal horn were markedly induced during early stage post-injury. Moreover, the maximal increase in BDNF mRNA expression in the DRG was observed at day 1 post-injury, and significantly elevated levels were sustained for at least 14 days. Four of five BDNF mRNA transcripts were up-regulated after nerve injury, and the most inducible transcript was exon I. Using a chromatin immunoprecipitation (ChIP) assay, we found that nerve injury promotes histone H3 and H4 acetylation, transcriptionally active modifications, at BDNF promoter I at day 1 post-injury, and the levels of histone acetylation remain elevated for at least 7 days. Taken together, our findings suggest that an initial increase in BDNF exon I expression controlled by epigenetic mechanisms might have a crucial role in the development of neuropathic pain. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.neuroscience.2013.02.053

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  • Permanent relief from intermittent cold stress-induced fibromyalgia-like abnormal pain by repeated intrathecal administration of antidepressants 査読

    Michiko Nishiyori, Hitoshi Uchida, Jun Nagai, Kohei Araki, Takehiro Mukae, Shiroh Kishioka, Hiroshi Ueda

    MOLECULAR PAIN   7   69   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SAGE PUBLICATIONS INC  

    Background: Fibromyalgia (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).
    Results: In 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.
    Conclusions: These results suggest that the repetitive intrathecal administration of antidepressants permanently cures ICS-induced FM pain in mice.

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  • Autotaxin and lysophosphatidic acid(1) receptor-mediated demyelination of dorsal root fibers by sciatic nerve injury and intrathecal lysophosphatidylcholine 査読

    Jun Nagai, Hitoshi Uchida, Yosuke Matsushita, Ryo Yano, Mutsumi Ueda, Masami Niwa, Junken Aoki, Jerold Chun, Hiroshi Ueda

    MOLECULAR PAIN   6   78   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Although neuropathic pain is frequently observed in demyelinating diseases such as Guillain-Barre syndrome and multiple sclerosis, the molecular basis for the relationship between demyelination and neuropathic pain behaviors is poorly understood. Previously, we found that lysophosphatidic acid receptor (LPA(1)) signaling initiates sciatic nerve injury-induced neuropathic pain and demyelination.
    Results: In the present study, we have demonstrated that sciatic nerve injury induces marked demyelination accompanied by myelin-associated glycoprotein (MAG) down-regulation and damage of Schwann cell partitioning of C-fiber-containing Remak bundles in the sciatic nerve and dorsal root, but not in the spinal nerve. Demyelination, MAG down-regulation and Remak bundle damage in the dorsal root were abolished in LPA(1) receptor-deficient (Lpar1(-/-)) mice, but these alterations were not observed in sciatic nerve. However, LPA-induced demyelination in ex vivo experiments was observed in the sciatic nerve, spinal nerve and dorsal root, all which express LPA(1) transcript and protein. Nerve injury-induced dorsal root demyelination was markedly attenuated in mice heterozygous for autotaxin (atx(+/-)), which converts lysophosphatidylcholine (LPC) to LPA. Although the addition of LPC to ex vivo cultures of dorsal root fibers in the presence of recombinant ATX caused potent demyelination, it had no significant effect in the absence of ATX. On the other hand, intrathecal injection of LPC caused potent dorsal root demyelination, which was markedly attenuated or abolished in atx(+/-) or Lpar1(-/-) mice.
    Conclusions: These results suggest that LPA, which is converted from LPC by ATX, activates LPA(1) receptors and induces dorsal root demyelination following nerve injury, which causes neuropathic pain.

    DOI: 10.1186/1744-8069-6-78

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  • Endocrine disrupting chemicals bind to a novel receptor, microtubule-associated protein 2, and positively and negatively regulate dendritic outgrowth in hippocampal neurons 査読

    Hayato Matsunaga, Kaori Mizota, Hitoshi Uchida, Takafumi Uchida, Hiroshi Ueda

    JOURNAL OF NEUROCHEMISTRY   114 ( 5 )   1333 - 1343   2010年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    P>The present study demonstrates a novel high-affinity neuronal target for endocrine disrupting chemicals (EDCs), which potentially cause psychological disorders. EDCs competitively inhibited the binding of bovine serum albumin-conjugated progesterone to recombinant human microtubule-associated protein 2C (rhMAP2C) with an inhibition constant at picomolar levels. In the rhMAP2C-stimulated tubulin assembly assay, agonistic enhancement was observed with dibutyl phthalate and pentachlorphenol and pregnenolone, while an inverse agonistic effect was observed with 4-nonylphenol. In contrast, progesterone and many of the EDCs, including bisphenol A, antagonized the pregnenolone-induced enhancement of rhMAP2C-stimulated tubulin assembly. These agonistic and inverse agonistic actions were not observed in tubulin assembly stimulated with delta 1-71 rhMAP2C, which lacks the steroid-binding site. Using a dark-field microscopy, pregnenolone and pentachlorphenol were observed to generate characteristic filamentous microtubules in a progesterone- or bisphenol A-reversible manner. In cultured hippocampal neurons, similar agonist-antagonist relationships were reproduced in terms of dendritic outgrowth. Fluorescent recovery after photobleaching of hippocampal neurons showed that pregnenolone and agonistic EDCs enhanced, but that 4-nonylphenol inhibited the MAP2-mediated neurite outgrowth in a progesterone- or antagonistic EDC-reversible manner. Furthermore, none of the examined effects were affected by mifepristone or ICI-182,786 i.e. the classical progesterone and estrogen receptor antagonists. Taken together, these results suggest that EDCs cause a wide variety of significant disturbances to dendritic outgrowth in hippocampal neurons, which may lead to psychological disorders following chronic exposure during early neuronal development.

    DOI: 10.1111/j.1471-4159.2010.06847.x

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  • Evidence for De Novo Synthesis of Lysophosphatidic Acid in the Spinal Cord through Phospholipase A(2) and Autotaxin in Nerve Injury-Induced Neuropathic Pain 査読

    Lin Ma, Hitoshi Uchida, Jun Nagai, Makoto Inoue, Junken Aoki, Hiroshi Ueda

    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS   333 ( 2 )   540 - 546   2010年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

    We previously reported that lysophosphatidic acid (LPA) initiates nerve injury-induced neuropathic pain and its underlying mechanisms. In addition, we recently demonstrated that intrathecal injection of LPA induces de novo LPA production through the action of autotaxin (ATX), which converts lysophosphatidylcholine to LPA. Here, we examined nerve injury-induced de novo LPA production by using a highly sensitive biological titration assay with B103 cells expressing LPA(1) receptors. Nerve injury caused high levels of LPA production in the ipsilateral sides of the spinal dorsal horn and dorsal roots, but not in the dorsal root ganglion, spinal nerve, or sciatic nerve. Nerve injury-induced LPA production reached its maximum at 3 h after injury, followed by a rapid decline by 6 h. The LPA production was significantly attenuated in ATX heterozygous mutant mice, whereas the concentration and activity of ATX in cerebrospinal fluid were not affected by nerve injury. On the other hand, the activities of cytosolic phospholipase A(2) (cPLA(2)) and calcium-independent phospholipase A(2) (iPLA(2)) were enhanced, with peaks at 1 h after injury. Both de novo LPA production and neuropathic pain-like behaviors were substantially abolished by intrathecal injection of arachidonyl trifluoromethyl ketone, a mixed inhibitor of cPLA(2) and iPLA(2), or bromoenol lactone, an iPLA(2) inhibitor, at 1 h after injury. However, administration of these inhibitors at 6 h after injury had no significant effect on neuropathic pain. These findings provide evidence that PLA(2)- and ATX-mediated de novo LPA production in the early phase is involved in nerve injury-induced neuropathic pain.

    DOI: 10.1124/jpet.109.164830

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  • Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain 査読

    Weijiao Xie, Hitoshi Uchida, Jun Nagai, Mutsumi Ueda, Jerold Chun, Hiroshi Ueda

    JOURNAL OF NEUROCHEMISTRY   113 ( 4 )   1002 - 1011   2010年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    P>Lysophosphatidic acid receptor (LPA(1)) signaling initiates neuropathic pain through demyelination of the dorsal root (DR). Although LPA is found to cause down-regulation of myelin proteins underlying demyelination, the detailed mechanism remains to be determined. In the present study, we found that a single intrathecal injection of LPA evoked a dose- and time-dependent down-regulation of myelin-associated glycoprotein (MAG) in the DR through LPA(1) receptor. A similar event was also observed in ex vivo DR cultures. Interestingly, LPA-induced down-regulation of MAG was significantly inhibited by calpain inhibitors (calpain inhibitor X, E-64 and E-64d) and LPA markedly induced calpain activation in the DR. The pre-treatment with calpain inhibitors attenuated LPA-induced neuropathic pain behaviors such as hyperalgesia and allodynia. Moreover, we found that sciatic nerve injury activates calpain activity in the DR in a LPA(1) receptor-dependent manner. The E-64d treatments significantly blocked nerve injury-induced MAG down-regulation and neuropathic pain. However, there was no significant calpain activation in the DR by complete Freund's adjuvant treatment, and E-64d failed to show anti-hyperalgesic effects in this inflammation model. The present study provides strong evidence that LPA-induced calpain activation plays a crucial role in the manifestation of neuropathic pain through MAG down-regulation in the DR.

    DOI: 10.1111/j.1471-4159.2010.06664.x

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  • NEURON-RESTRICTIVE SILENCER FACTOR CAUSES EPIGENETIC SILENCING OF K(V)4.3 GENE AFTER PERIPHERAL NERVE INJURY 査読

    H. Uchida, K. Sasaki, L. Ma, H. Ueda

    NEUROSCIENCE   166 ( 1 )   1 - 4   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Peripheral nerve injury causes a variety of alterations in pain-related gene expression in primary afferent, which underlie the neuronal plasticity in neuropathic pain. One of the characteristic alterations is a long-lasting down-regulation of voltage-gated potassium (K-v) channel, including K(v)4.3, in the dorsal root ganglion (DRG). The present study showed that nerve injury reduces the messenger RNA (mRNA) expression level of K(v)4.3 gene, which contains a conserved neuron-restrictive silencer element (NRSE), a binding site for neuron-restrictive silencer factor (NRSF). Moreover, we found that injury causes an increase in direct NRSF binding to K(v)4.3-NRSE in the DRG, using chromatin immunoprecipitation (Chip) assay. Chip assay further revealed that acetylation of histone H4, but not H3, at K(v)4.3-NRSE is markedly reduced at day 7 post-injury. Finally, the injury-induced K(v)4.3 downregulation was significantly blocked by antisense-knockdown of NRSF. Taken together, these data suggest that nerve injury causes an epigenetic silencing of K(v)4.3 gene mediated through transcriptional suppressor NRSF in the DRG. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.neuroscience.2009.12.021

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  • Epigenetic Gene Silencing Underlies C-Fiber Dysfunctions in Neuropathic Pain 査読

    Hitoshi Uchida, Lin Ma, Hiroshi Ueda

    JOURNAL OF NEUROSCIENCE   30 ( 13 )   4806 - 4814   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Peripheral nerve injury causes neuropathic pain, which is characterized by the paradoxical sensations of positive and negative symptoms. Clinically, negative signs are frequently observed; however, their underlying molecular mechanisms are largely unknown. Dysfunction of C-fibers is assumed to underlie negative symptoms and is accompanied by long-lasting downregulation of Na(v)1.8 sodium channel and mu-opioid receptor (MOP) in the dorsal root ganglion (DRG). In the present study, we found that nerve injury upregulates neuron-restrictive silencer factor (NRSF) expression in the DRG neurons mediated through epigenetic mechanisms. In addition, chromatin immunoprecipitation analysis revealed that nerve injury promotes NRSF binding to the neuron-restrictive silencer element within MOP and Na(v)1.8 genes, thereby causing epigenetic silencing. Furthermore, NRSF knockdown significantly blocked nerve injury-induced downregulations of MOP and Na(v)1.8 gene expressions, C-fiber hypoesthesia, and the losses of peripheral morphine analgesia and Na(v)1.8-selective blocker-induced hypoesthesia. Together, these data suggest that NRSF causes pathological and pharmacological dysfunction of C-fibers, which underlies the negative symptoms in neuropathic pain.

    DOI: 10.1523/JNEUROSCI.5541-09.2010

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  • Prothymosin alpha as robustness molecule against ischemic stress to brain and retina 査読

    Hiroshi Ueda, Hayato Matsunaga, Hitoshi Uchida, Mutsumi Ueda

    THYMOSINS IN HEALTH AND DISEASE   1194   20 - 26   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Following stroke or traumatic damage, neuronal death via both necrosis and apoptosis causes loss of functions, including memory, sensory, perception, and motor skills. As necrosis has the nature to expand, while apoptosis stops the cell death cascade in the brain, necrosis is considered to be a promising target for rapid treatment for stroke. We identified the nuclear protein, prothymosin alpha (ProT alpha) from the conditioned medium of serum-free culture of cortical neurons as a key protein-inhibiting necrosis. In the culture of cortical neurons in the serum-free condition without any supplements, ProT alpha inhibited the necrosis, but caused apoptosis. In the ischemic brain or retina, ProT alpha showed a potent inhibition of both necrosis and apoptosis. By use of anti-brain-derived neurotrophic factor or anti-erythropoietin IgG, we found that ProT alpha inhibits necrosis, but causes apoptosis, which is in turn inhibited by ProT alpha-induced neurotrophins under the condition of ischemia. From the experiment using anti-ProT alpha IgG or antisense oligonucleotide for ProT alpha, it was revealed that ProT alpha has a pathophysiological role in protecting neurons in stroke.

    DOI: 10.1111/j.1749-6632.2010.05466.x

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  • Lysophosphatidic acid-3 receptor-mediated feed-forward production of lysophosphatidic acid: an initiator of nerve injury-induced neuropathic pain 査読

    Lin Ma, Hitoshi Uchida, Jun Nagai, Makoto Inoue, Jerold Chun, Junken Aoki, Hiroshi Ueda

    MOLECULAR PAIN   5   64   2009年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: We previously reported that intrathecal injection of lysophosphatidylcholine (LPC) induced neuropathic pain through activation of the lysophosphatidic acid (LPA)-1 receptor, possibly via conversion to LPA by autotaxin (ATX).
    Results: We examined in vivo LPA-induced LPA production using a biological titration assay with B103 cells expressing LPA(1) receptors. Intrathecal administration of LPC caused time-related production of LPA in the spinal dorsal horn and dorsal roots, but not in the dorsal root ganglion, spinal nerve or sciatic nerve. LPC-induced LPA production was markedly diminished in ATX heterozygotes, and was abolished in mice that were deficient in LPA(3), but not LPA(1) or LPA(2) receptors. Similar time-related and LPA(3) receptor-mediated production of LPA was observed following intrathecal administration of LPA. In an in vitro study using spinal cord slices, LPA-induced LPA production was also mediated by ATX and the LPA(3) receptor. Intrathecal administration of LPA, in contrast, induced neuropathic pain, which was abolished in mice deficient in LPA(1) or LPA(3) receptors.
    Conclusion: These findings suggest that feed-forward LPA production is involved in LPA-induced neuropathic pain.

    DOI: 10.1186/1744-8069-5-64

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  • Profiling of BoNT/C3-reversible gene expression induced by lysophosphatidic acid: ephrinB1 gene up-regulation underlying neuropathic hyperalgesia and allodynia 査読

    Hitoshi Uchida, Misaki Matsumoto, Hiroshi Ueda

    NEUROCHEMISTRY INTERNATIONAL   54 ( 3-4 )   215 - 221   2009年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Lysophosphatidic acid (LPA) signaling, through LPA(1) receptor and its downstream RhoA, has been reported to initiate nerve injury-induced neuropathic pain. In the present study, we performed gene expression profiling of the dorsal root ganglion (DRG) to identify genes induced by intrathecal injection of LPA in a botulinum toxin C3 (BoNT/C3)-reversible manner. We selected and functionally characterized ephrinB1 from 82 identified genes as a potential gene involved in pain transmission, since ephrinB1 is implicated to modulate N-methyl-D-aspartate (NMDA) receptor functions in spinal pain transmission. The LPA-induced and BoNT/C3-reversible ephrinB1 gene expression was confirmed by quantitative real-time PCR. Furthermore, treatments with an antisense oligodeoxynucleotide for ephrinB1 largely abolished the LPA-induced thermal hyperalgesia and allodynia in response to mechanical or A beta-fiber-mediated electrical stimuli on day 1 after the injection. In addition, intrathecal treatment with a soluble ligand, ephrinB1-Fc, caused similar neuropathic pain-like behaviors in a manner that was reversible by the NMDA receptor antagonist MK-801. These results suggest that ephrinB1 plays a crucial role in LPA-induced neuropathic pain. In addition, the present study may provide a new strategy to identify unique neuropathic pain-related genes. (C) 2008 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.neuint.2008.11.004

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  • Novel type of G(q/11) protein-coupled neurosteroid receptor sensitive to endocrine disrupting chemicals in mast cell line (RBL-2H3) 査読

    K Mizota, A Yoshida, H Uchida, R Fujita, H Ueda

    BRITISH JOURNAL OF PHARMACOLOGY   145 ( 4 )   545 - 550   2005年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    1 Agonistic neurosteroids, including pregnenolone, dehydroepiandrosterone and its sulfate (DHEAS), caused rapid degranulation in measurements of beta-hexosaminidase (beta-HEX) release from a mast cell line, RBL-2H3. This degranulation was blocked by BSA-conjugated progesterone (PROG-BSA) or 17 beta-estradiol, both of which are antagonistic neurosteroids.
    2 DHEAS-induced beta-HEX release was blocked by U-73122 or xestospongin C, but not by PTX or EGTA. DHEAS-induced beta-HEX release was also abolished by G(q/11)-AS, but not by G(q/11)-MS. Pharmacological analyses revealed that the neurosteroids stimulated a putative membrane receptor through activation of the novel G(q/11) and phospholipase C.
    3 While representative endocrine-disrupting chemicals (EDCs) did not show any degranulation or nocifensive actions by themselves, they blocked the DHEAS-induced degranulation.
    4 The binding of a PROG-BSA-fluorescein isothiocyanate conjugate (PROG-BSA-FITC) to cells was inhibited by neurosteroids and EDCs.
    5 In the algogenic-induced biting and licking responses test, DHEAS caused agonistic nocifensive actions in a dose-dependent manner between 1 and 10 fmol (i.pl.). DHEAS-induced nocifensive actions were abolished by PROG-BSA or nonylphenol.
    6 Taken together, these results suggest that a G(q/11)-coupled neurosteroid receptor may regulate the neuroimmunological activity related to sensory stimulation and that some EDCs have antagonistic actions for this receptor.

    DOI: 10.1038/sj.bjp.0706213

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  • Neurosteroid-induced hyperalgesia through a histamine release is inhibited by progesterone and p,p '-DDE, an endocrine disrupting chemical 査読

    H Uchida, K Mizuno, A Yoshida, H Ueda

    NEUROCHEMISTRY INTERNATIONAL   42 ( 5 )   401 - 407   2003年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    The intraplantar injection of dehydroepiandrosterone sulfate (DHEAS), a representative neurosteroid, showed hyperalgesia in the Hargreaves' thermal or automatic paw-pressure mechanical nociception test. The DHEAS-induced hyperalgesia was abolished by diphenhydramine (DPH), a H-1 histamine (His) receptor antagonist, as well as the hyperalgesia induced by His or compound 48/80, a mast cell degranulating agent. The DHEAS-induced hyperalgesia was also blocked by progesterone (PROG), another type of neurosteroid and a putative neurosteroid receptor antagonist. Neither DPH nor PROG showed any changes in the thermal threshold. On the other hand, endocrine disrupting chemicals (EDCs) are known to disrupt reproductive system in wild-lives and humans through the disturbance of the endocrine homeostasis. In this study, the flexor responses induced by intraplantar injection of DHEAS were blocked by p,p'-DDE, an EDC as well as by PROG in the algogenics-induced nociceptive flexor responses test (ANF test) in mice. Similarly, p,p'-DDE blocked the DHEAS-induced hyperalgesia in Hargreaves' thermal nociception test. Besides the hyperalgesic actions, DHEAS increased vascular permeability as measured with Evans blue plasma extravasation. Consistent with behavioral studies, it was blocked by DPH, PROG, and p,p'-DDE. These results suggest that DHEAS has significant hyperalgesic and vasodilatory actions through histamine release, and these actions were reversible by PROG and an EDC. (C) 2002 Elsevier Science Ltd. All rights reserved.

    DOI: 10.1016/S0197-0186(02)00135-3

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  • Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception 査読

    A Dobolyi, H Ueda, H Uchida, M Palkovits, TB Usdin

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   99 ( 3 )   1651 - 1656   2002年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    The parathyroid hormone 2 (PTH2) receptor's anatomical distribution suggests that, among other functions, it may be involved in modulation of nociception. We localized PTH2 receptor protein to spinal cord lamina 11 and showed that it is synthesized by subpopulations of primary sensory neurons and intrinsic spinal cord dorsal horn neurons. Tuberoinfundibular peptide of 39 residues (TIP39) selectively activates the PTH2 receptor. Intraplantar microinjection of TIP39 caused a paw-withdrawal response and intrathecal injection caused scratching, biting, and licking, a nocifensive response. Intrathecal administration of a TIP39 antibody decreased sensitivity in tail-flick and paw-pressure assays. Intrathecal administration of TIP39 potentiated responses in these assays. We determined the sequence of TIP39's precursor and found that mRNA encoding TIP39 and TIP39-like immuno reactivity is concentrated in two brainstem areas, the subparafascicular area and the caudal paralemniscal nucleus. Cells in these areas project to the superficial dorsal horn of the spinal cord. Our data suggest that TIP39 released from supraspinal fibers potentiates aspects of nociception within the spinal cord.

    DOI: 10.1073/pnas.042416199

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MISC

講演・口頭発表等

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受賞

  • 優秀演題

    2018年6月   第40回 日本疼痛学会  

    内田 仁司

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  • 優秀演題

    2014年6月   第36回 日本疼痛学会  

    内田 仁司

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  • Hot Topics

    2010年11月   第40回 北米神経科学学会  

    内田 仁司

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  • 年会優秀発表賞

    2009年3月   第82回 日本薬理学会年会  

    内田 仁司

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共同研究・競争的資金等の研究

  • 神経障害性疼痛におけるRNA編集の役割解明

    2017年4月 - 2019年3月

    日本学術振興会  科学研究費補助金 (若手研究(B)) 

    内田 仁司

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    担当区分:研究代表者  資金種別:競争的資金

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  • 神経障害性疼痛におけるエピジェネティックサイレンシングの統合的理解

    2014年4月 - 2016年3月

    日本学術振興会  科学研究費補助金 (若手研究(B)) 

    内田 仁司

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    担当区分:研究代表者  資金種別:競争的資金

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  • LPAプライミングとiPS細胞を用いた慢性疼痛病態神経回路要素の再構成と創薬

    2014年4月 - 2015年3月

    日本学術振興会  科学研究費補助金 (基盤研究(A)) 

    植田 弘師

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    資金種別:競争的資金

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  • 難治性神経因性疼痛を担うエピジェネティクス異常とその調節機構の解明

    2011年4月 - 2014年3月

    日本学術振興会  科学研究費補助金(特別研究員奨励費) 

    内田 仁司

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    担当区分:研究代表者  資金種別:競争的資金

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  • 神経障害性疼痛における転写因子RESTの翻訳後修飾とその機能の解明

    2011年4月 - 2012年3月

    関西医科大学  平成23年度学内研究助成D1 

    内田 仁司

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    担当区分:研究代表者  資金種別:競争的資金

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  • 慢性疼痛を制御するエピジェネティクス:転写因子NRSF/RESTの機能解明

    2011年2月 - 2012年1月

    財団法人 東京生化学研究会  平成22年度 研究奨励金 

    内田 仁司

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    担当区分:研究代表者  資金種別:競争的資金

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  • 脂質シグナリングによる痛みの記憶化:エピジェネティクス制御機構の解明

    2010年4月 - 2011年3月

    長崎大学  平成22年度 大学高度化推進経費 若手研究者への研究支援事業 

    内田 仁司

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    担当区分:研究代表者  資金種別:競争的資金

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  • 脂質シグナリングによる痛みの記憶化:エピジェネティクス制御機構の解明

    2010年4月 - 2011年3月

    日本学術振興会  科学研究費補助金 (基盤研究(C)) 

    内田 仁司

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    担当区分:研究代表者  資金種別:競争的資金

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  • ストレス性精神疾患の可視化とナノメディシン

    2009年4月 - 2010年3月

    日本学術振興会  科学研究費補助金 (特定領域研究) 

    植田 弘師

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    資金種別:競争的資金

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  • 脱髄性神経損傷に起因する難治性神経因性疼痛の治療標的分子の同定

    2009年4月 - 2010年3月

    日本学術振興会  科学研究費補助金 (基盤研究(S)) 

    植田 弘師

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    資金種別:競争的資金

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