Visceral pain and activation of MAPK in sensory neurons after noxious gastric distension

• Project/Area Number: 19590740
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hyogo College of Medicine
• Principal Investigator: TANAKA Junji Hyogo College of Medicine, 医学部, 助教 (90412022)
• Co-Investigator(Kenkyū-buntansha): OBATA Koichi 兵庫医科大学, 医学部, 准教授 (70368538)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: TRPV1 / TRPA1 / ASIC3 / DRG / NG / MAPK / ERK / p38 / EPK / JNK

Research Abstract

胃が痛い、胃が重いなどの上腹部を中心とする症状を訴える患者は多いが、このような症状を有する約半数の患者にはその原因を説明できる器質的疾患が認められない。このような症状発現の機序の一つとして内臓知覚過敏の存在が指摘されている。胃の知覚は一般的に脊髄神経系を介する経路と、迷走神経を介する経路とが考えられているが、この2つの異なる経路の働きの違いなど、内臓知覚に対する研究は少なく、未だ不明な点が多い。一方、MAPK の一員であるERK1/2やp38 MAPKは、細胞内情報伝達に関与し、その活性化が脊髄後根神経節(dorsal rootganglion: DRG)や脊髄などで認められ、痛みの発生やそれに伴う変化に重要であるとされている。最近、我々はラットの胃に侵害性伸展刺激を加えると、DRGおよび迷走下神経節(nodose ganglion : NG)においてERK1/2の活性化だけではなくp38 MAPKの活性化も誘導されることを見いだした。侵害性伸展刺激によるこれらMAPKのリン酸化は、2分がピークであり、TRPV1、TRPA1、ASIC3陽性の小型ニューロンが中心であった。DRGだけではなく、NGにおいてもERK1/2やp38 MAPKの活性化がみられることを考えると、機械的刺激による侵害受容に迷走神経系も関与している可能性が考えられる。内臓知覚における脊髄神経系と迷走神経系の役割の相違については更なる検討を要するものの、我々の知見は急性内臓痛発生のメカニズムには脊髄ニューロンだけではなく、一次知覚ニューロンにおけるMAPKの活性化も重要な役割を担っていること、さらに多種多様の侵害刺激に対して反応する一次知覚ニューロンの活性化を細胞内情報伝達分子の動態より解析できる可能性を示唆している。これらの成果はGastroenterology等、数多くの国際誌に発表した。

Research Products

• [Journal Article] IL-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. (2008)
  • Author(s): Miyoshi, K., Obata, K., Kondo, T., Okamura, H. and Noguchi, K.
  • Journal Title: J. Neurosci. 28 Pages: 12775-12787
  • Peer Reviewed
• [Journal Article] Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. (2008)
  • Author(s): Katsura, H., Obata, K., Miyoshi, K., Kondo, T., Yamanaka, H., Kobayashi, K., Dai, Y., Fukuoka, T., Sakagami, M. and Noguchi, K.
  • Journal Title: Glia 56 Pages: 723-733
  • Peer Reviewed
• [Journal Article] P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain (2008)
  • Author(s): Kobayashi, K., Yamanaka, H., Fukuoka, T., Dai, Y., Obata, K. and Noguchi, K.
  • Journal Title: J. Neurosci. 12 Pages: 2892-902
  • Peer Reviewed
• [Journal Article] Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury. (2008)
  • Author(s): Obata, K., Katsura, H., Miyoshi, K., Kondo, T., Yamanaka, H., Kobayashi, K., Dai, Y., Fukuoka, T., Akira, S. and Noguchi K.
  • Journal Title: J. Neurochem. 105 Pages: 2249-2259
  • Peer Reviewed
• [Journal Article] Activation of extracellular signal-regulated protein kinase in sensory neurons after noxious gastric distention and its involvement in acute visceral pain in rats. (2008)
  • Author(s): Sakurai, J., Obata, K., Ozaki, N., Tokunaga, A., Kobayashi, K., Yamanaka, H., Dai, Y., Kondo, T., Miyoshi, K., Sugiura, Y., Matsumoto, T., Miwa, H. and Noguchi, K.
  • Journal Title: Gastroenterology. 134(4) Pages: 1094-103
  • Peer Reviewed
• [Journal Article] Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. (2008)
  • Author(s): Miyoshi, K., et. al.
  • Journal Title: J. Neurosci. 28 Pages: 12775-12787
  • Peer Reviewed
• [Journal Article] Comparative study of the distribution of the alpha-subunits of voltage-gated sodium channels in normal and axotomized rat dorsal root ganglion neurons. (2008)
  • Author(s): Fukuoka, T., et. al.
  • Journal Title: J. Comp. Neurol. 510 Pages: 188-206
  • Peer Reviewed
• [Journal Article] Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. (2008)
  • Author(s): Katsura, H., et. al.
  • Journal Title: Glla 56 Pages: 723-733
  • Peer Reviewed
• [Journal Article] P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. (2008)
  • Author(s): Kobayashi, K., et. al.
  • Journal Title: J. Neurosci. 28 Pages: 2892-2902
  • Peer Reviewed
• [Journal Article] Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1 : a molecular mechanism of inflammatory pain. (2008)
  • Author(s): Wang, s., et, al.
  • Journal Title: Brain 131 Pages: 1241-1251
  • Peer Reviewed
• [Journal Article] Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury. (2008)
  • Author(s): Obata, K., et. al.
  • Journal Title: J. Neurochem. 105 Pages: 2249-2259
  • Peer Reviewed
• [Journal Article] Activation of extracellular signal-regulated protein kinase in sensory neurons after noxious gastric distention and its involvement in acute visceral pain in rats. (2008)
  • Author(s): Sakurai, J., et. al.
  • Journal Title: Gastroenterology 134 Pages: 1094-1103
  • Peer Reviewed
• [Journal Article] Differential activation of p38 and extracellular signal-regulated kinase in spinal cord in a model of bee venom-induced inflammation and hyperalgesia. (2008)
  • Author(s): Cui, X. Y., et. al.
  • Journal Title: Mol. Pain Pages: 4-17
  • Peer Reviewed
• [Journal Article] 神経障害性疼痛における一次知覚ニューロンの役割 (2008)
  • Author(s): 小畑浩一, 他
  • Journal Title: ペインクリニック 29 Pages: 170-178
  • Peer Reviewed
• [Journal Article] 神経因性疼痛の分子メカニズム (2008)
  • Author(s): 小畑浩一, 他
  • Journal Title: Brain and Nerve 60 Pages: 483-492
  • Peer Reviewed
• [Journal Article] Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury (2008)
  • Author(s): Katsura, H., et. al.
  • Journal Title: Glia (In press)
  • Peer Reviewed
• [Journal Article] P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain (2008)
  • Author(s): Kobayashi, K., et. al.
  • Journal Title: J.Neurosci 28 Pages: 2892-2902
  • Peer Reviewed
• [Journal Article] Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1:a molecular mechanism of inflammatory pain (2008)
  • Author(s): Wang, S., et. al.
  • Journal Title: Brain (In press)
  • Peer Reviewed
• [Journal Article] Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. (2007)
  • Author(s): Dai, Y., Wang, S., Tominaga, M., Yamamoto, S., Fukuoka, T., Higashi, T., Kobayashi, K., Obata, K., Yamanaka, H. and Noguchi, K.
  • Journal Title: J. Clin. Invest. 117 Pages: 1979-1987
  • Peer Reviewed
• [Journal Article] Activation of extracellular signal-regulated protein kinases 5 in primary afferent neurons contributes to heat and cold hyperalgesia after inflammation. (2007)
  • Author(s): Katsura, H., Obata, K., Mizushima, T., Sakurai, J., Kobayashi, K., Yamanaka, H., Dai, Y., Fukuoka, T., Sakagami, M. and Noguchi, K.
  • Journal Title: J. Neurochem 102 Pages: 1614-1624
  • Peer Reviewed
• [Journal Article] Roles of extracellular signal-regulated protein kinases 5 in spinal microglia and primary sensory neurons for neuropathic pain. (2007)
  • Author(s): Obata, K., Katsura, H., Mizushima, T., Sakurai, J., Kobayashi, K., Yamanaka, H., Dai, Y., Fukuoka, T. and Noguchi, K.
  • Journal Title: J. Neurochem. 102 Pages: 1569-1584
  • Peer Reviewed
• [Journal Article] Alternation of the cell adhesion molecule L1 expression in a specific subset of primary afferent neurons contributes to neuropathic pain. (2007)
  • Author(s): Yamanaka, H., Obata, K., Kobayashi, K., Dai, Y., Fukuoka, T., and Noguchi, K.
  • Journal Title: Eur. J. Neurosci 25 Pages: 1097-1111
  • Peer Reviewed
• [Journal Article] Intensity-dependent activation of extracellular signal-regulated protein kinases 5 in sensory neurons contributes to pain hypersensitivity (2007)
  • Author(s): Mizushima, T., et. al.
  • Journal Title: J.Pharmacol.Exp.Ther 321 Pages: 28-34
  • Peer Reviewed
• [Journal Article] Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal roott injury (2007)
  • Author(s): Kozai, T., et. al.
  • Journal Title: Glia 55 Pages: 595-603
  • Peer Reviewed
• [Journal Article] Frequency-dependent ERK phosphorylation in spinal neurons by electric stimutation of the sciatic nerve and the role in electrophysiological activity (2007)
  • Author(s): Fukui, T., et. al.
  • Journal Title: Mol.Pain 3.18
  • Peer Reviewed
• [Journal Article] Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain (2007)
  • Author(s): Dai, Y., et. al.
  • Journal Title: J.Clin.Invest 117 Pages: 1979-1987
  • Peer Reviewed
• [Journal Article] Activation of extracellular signal-regulated protein kinases 5 in primary afferent neurons contributes to heat and cold hyperalgesia after inflammation (2007)
  • Author(s): Katsura, H., et. al.
  • Journal Title: J.Neurochem 102 Pages: 1614-1624
  • Peer Reviewed
• [Journal Article] Roles of extracellular signal-regulated protein kinases 5 in spinal microglia and primary sensory neurons for neuropathic pain (2007)
  • Author(s): Obata, K., et. al.
  • Journal Title: J.Neurochem 102 Pages: 1569-1584
  • Peer Reviewed
• [Journal Article] Activation of fibroblast growth factor receptor by axotomy,through downstream p38 in dorsal root ganglion,contributes to neuropathic pain (2007)
  • Author(s): Yamanaka, H., et. al.
  • Journal Title: Neuroscience 150 Pages: 202-211
  • Peer Reviewed
• [Presentation] IL-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. (2008)
  • Author(s): Miyoshi, K., et. al.
  • Organizer: The 38th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Washington D. C.
  • Year and Date: 2008-11-17
• [Presentation] TRPA1 mediates gastric distension-induced visceral pain in rats. (2008)
  • Author(s): Kondo, T., et. al.
  • Organizer: The 38th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Washington D. C.
  • Year and Date: 2008-11-16
• [Presentation] ラット胃伸展刺激後の急性内臓痛とTRPA1を介したERK の活性化. (2008)
  • Author(s): 近藤隆, 小畑浩一, 櫻井淳, 三輪洋人, 野口光一
  • Organizer: 第1回J-FD研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-11-08
• [Presentation] ラット胃伸展刺激に伴う内臓痛におけるTRPA1 の関与 (2008)
  • Author(s): 近藤隆, 小畑浩一, 櫻井淳, 三輪洋人, 野口光一
  • Organizer: 第7回日本Neurogastroenterology(神経消化器病)学会
  • Place of Presentation: 東京
  • Year and Date: 2008-09-30
• [Presentation] 脊髄マイクログリアにおけるTLR3の活性化とアロディニア (2008)
  • Author(s): 小畑 浩一
  • Organizer: 第113回日本解剖学会総会
  • Place of Presentation: 大分
  • Year and Date: 2008-03-29
• [Presentation] IL-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. (2008)
  • Author(s): Miyoshi, K., Obata, K., and Noguchi, K.
  • Organizer: The 38th Annual Meeting Society for Neuroscience,
  • Place of Presentation: Washington, DC., U.S.A.
• [Presentation] TRPA1 mediates gastric distension-induced visceral pain in rats. (2008)
  • Author(s): Kondo, T., Obata, K., Miyoshi, K., Sakurai, J., Miwa, H. and Noguchi, K.
  • Organizer: The 38th Annual Meeting Society for Neuroscience,
  • Place of Presentation: Washington, DC., U.S.A
• [Presentation] ラット胃伸展刺激に伴う内臓痛におけるTRPA1の関与 (2008)
  • Author(s): 近藤隆, 小畑浩一, 櫻井淳, 三輪洋人, 野口光一
  • Organizer: 第50回日本消化器病学会大会
  • Place of Presentation: 東京
• [Presentation] ラット胃伸展刺激後の一次知覚ニューロンにおけるp38MAPKの活性化 (2008)
  • Author(s): 近藤隆, 小畑浩一, 櫻井淳, 三輪洋人, 野口光一
  • Organizer: 第30回日本疼痛学会
  • Place of Presentation: 福岡
• [Presentation] TRPA1はラット胃伸展刺激後の急性内臓痛に関与する (2008)
  • Author(s): 近藤隆, 小畑浩一, 三輪洋人, 野口光一
  • Organizer: 第31回日本神経科学大会
  • Place of Presentation: 東京
• [Presentation] ラット胃の伸展刺激によるERK1/2の活性化 (2007)
  • Author(s): 桜井 淳
  • Organizer: 第6回日本Neurogastroenterology学会
  • Place of Presentation: 大阪
  • Year and Date: 2007-11-03
• [Presentation] ラット胃の伸展刺激による脊髄神経系の解剖 (2007)
  • Author(s): 桜井 淳
  • Organizer: 第49回日本消化器病学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2007-10-18
• [Presentation] 脊髄マイクログリアにおけるTLR3の活性化とアロディニア (2007)
  • Author(s): 小畑 浩一
  • Organizer: 第29回日本疼痛学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-07-07
• [Presentation] Activation of Toll-like receptor 3 in spinal microglia is required for tactile allodynia after nerve injury. (2007)
  • Author(s): Obata, K., Katsura, H., Miyoshi, K. and Noguchi, K.
  • Organizer: 37th Annual Meeting Society for Neuroscience
  • Place of Presentation: San Diego, U.S.A.
• [Presentation] 脊髄マイクログリアにおけるTLR3の活性化と神経因性疼痛 (2007)
  • Author(s): 小畑浩一, 野口光一
  • Organizer: 第30回日本神経科学大会
  • Place of Presentation: 横浜
• [Presentation] 痛みのターゲットは末梢か中枢か?慢性痛はどこを治療したらいいか (2007)
  • Author(s): 小畑 浩一
  • Organizer: 第5回整形外科痛みを語る会
  • Place of Presentation: 東京
• [Presentation] Activation of Toll-like receptor 3 in spinal microglia is required for tactile allodynia after nerve injury (2007)
  • Author(s): Obata, K., et. al.
  • Organizer: 37th Annual Meeting Society for Neuroscience
  • Place of Presentation: San Diego
• [Presentation] TAK1 upregulation in spinal astrocytes contributes to tactile allodynia after nerve injury (2007)
  • Author(s): Katsura, H., et. al.
  • Organizer: 37th Annual Meeting Society for Neuroscience
  • Place of Presentation: San Diego
• [Presentation] Changes in functions of glutamate receptor and its modulators in the spinal cordobtained from ethanol-dependent rats with painful neuropathy (2007)
  • Author(s): Miyoshi, K
  • Organizer: 37th Annual Meeting Society for Neuroscience
  • Place of Presentation: San Diego
• [Presentation] 脊髄アストロサイトにおけるTAK1の発現上昇とアロディニア (2007)
  • Author(s): 桂 弘和
  • Organizer: 第30回日本神経科学大会
  • Place of Presentation: 横浜
• [Book] 痛みのメカニズム.運動器の痛み診療ハンドブック,(山下敏彦 編) (2007)
  • Author(s): 小畑浩一, 野口光一
  • Publisher: 南江堂
• [Book] 痛みのメカニズム, 運動器の痛み診療ハンドブック(山下 敏彦編) (2007)
  • Author(s): 小畑 浩一
  • Total Pages: 354
  • Publisher: 南江堂