Role of MAP kinase family in the peripheral sensitization in a model of temporomandibular joint pain

• Project/Area Number: 19592330
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Hyogo College of Medicine
• Principal Investigator: TOKUNAGA Atsushi Hyogo College of Medicine, 医学部, 非常勤講師 (70254521)
• Co-Investigator(Kenkyū-buntansha): NOGUCHI Koichi 兵庫医科大学, 医学部, 教授 (10212127)
• 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: 顎関節 / 炎症痛 / MAP キナーゼ / ERK / PAR2 / TRPA1 / 疼痛 / MAPキナーゼ / NGF / ATP受容体

Research Abstract

「末梢感作」に同期したMAPKのリン酸化と、自発痛ではなく動作に伴う疼痛を特徴とする顎関節の疼痛の関連に着目した研究であり、目的としては顎関節痛モデル動物において
1)痛みを起こす刺激がMAPKを活性化するのか。
2)MAPK は末梢で何を標的としているのか、さらに
3)MAPKを末梢で阻害することで顎関節痛を改善し得るのか、を解明するのが目的である。顎関節痛モデル動物におけるMAPKの活性化の検討するために、起炎剤(complete Freund's adjuvant : CFA)を用いて、顎関節局所の炎症モデルを作成し、滑膜や軟骨での末梢神経終末でMAPK(ERK, p38,JNK)のリン酸化を検討した。リン酸化ERKの染色は、三叉神経節内のサテライト細胞及び小型を中心とした神経細胞に見られた。顎関節炎モデルの炎症側三叉神経節での小型細胞の染色が、反対側に比べて増加しており現在定量化を進めている。
また、炎症痛のメカニズム解明のため、末梢神経の感作機構を探る研究として、PAR2(proteinase activated receptor)による痛みチャネルであるTRPA1の感作機構の実験を施行した。その結果、PAR2の活性化の下流に存在するPKA とPKC のシグナル伝達系の両方がTRPA1の感作メカニズムに重要であることを発見した。この結果は一流国際誌に発表できるよう論文準備中である。

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] 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., Kobayashi, K., Yamanaka, H., Obata, K., Dai, Y. and Noguchi, K.
  • Journal Title: J. Comp. Neurol. 10, 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., 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] Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1 : a molecular mechanism of inflammatory pain (2008)
  • Author(s): Wang, S., Dai, Y., Fukuoka, T., Yamanaka, H., Kobayashi, K., Obata, K., Cui, X., Tominaga, M. and Noguchi, K.
  • Journal Title: Brain. 131(Pt5) 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., 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] 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, XY., Dai, Y., Wang. SL., Yamanaka, H., Kobayashi, K., Obata, K., Chen, J. and Noguchi, K.
  • Journal Title: Mol Pain. 30:4(1) Pages: 17-17
  • Peer Reviewed
• [Journal Article] lnterleukin-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 iniury. (2008)
  • Author(s): Katsura, H., et. al.
  • 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., 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 fibroblast growth factor receptor by axotomy, through downstream p38 in dorsal root ganglion, contributes to neuropathic pain. (2007)
  • Author(s): Yamanaka, H., Obata, K., Kobayashi, K., Dai, Y., Fukuoka, T. and Noguchi, K.
  • Journal Title: Neuroscience 150 Pages: 202-211
  • Peer Reviewed
• [Journal Article] Frequency-dependent ERK phosphorylation in spinal neurons by electric stimulation of the sciatic nerve and the role in electrophysiological activity. (2007)
  • Author(s): Fukui, T., Dai, Y., Iwata, K., Kamo, H., Yamanaka, H., Obata, K., Kobayashi, K., Wang, S., Cui, X., Yoshiya, S. and Noguchi, K.
  • Journal Title: Mol. Pain 3 Pages: 18-18
  • 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] Intensity-dependent activation of extracellular signal-regulated protein kinases 5 in sensory neurons contributes to pain hypersensitivity. (2007)
  • Author(s): Mizushima, T., Obata, K., Katsura, H., Sakurai, J., Kobayashi, K., Yamanaka, H., Dai, Y., Fukuoka, T., Mashimo, T. and Noguchi, K.
  • 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 root injury. (2007)
  • Author(s): Kozai, T., Yamanaka, H., Dai, Y., Obata, K., Kobayashi, K., Mashimo, T. and Noguchi, K.
  • Journal Title: Glia 55 Pages: 595-603
  • Peer Reviewed
• [Journal Article] Alternation of the cell adhesion molecule L1 expression in a specific subset of primary afferent neurons contributes to neuropathic pain. Eur. (2007)
  • Author(s): Yamanaka, H., Obata, K., Kobayashi, K., Dai, Y., Fukuoka, T., and Noguchi, K.
  • Journal Title: J. Neurosci, 25 Pages: 1097-1111
  • Peer Reviewed
• [Journal Article] Axotomy increases plasma membrane Ca^<2+> pump isoform4 in primary afferent neurons. (2007)
  • Author(s): Ogura, H., Tachibana, T., Yamanaka, H., Kobayashi, K., Obata, K., Dai, Y., Yoshiya, S. and Noguchi, K.
  • Journal Title: Neuroreport 18 Pages: 17-22
  • Peer Reviewed
• [Journal Article] Intensity-dependent activation of extracellular signal-regulated protein kinases 5 in sensory neurons contributes to pain hvpersensitivity (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 root 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 stimulation 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] TRP channels and nociception. (2008)
  • Author(s): Noguchi, K.
  • Organizer: 12th World Congress on Pain
  • Place of Presentation: Glasgow
  • Year and Date: 2008-08-22
• [Presentation] MAP kinase regulation of pain : peripheral, central and glial mechanisms. (2008)
  • Author(s): Noguchi, K.
  • Organizer: 12th World Congress on Pain
  • Place of Presentation: Glasgow
  • Year and Date: 2008-08-18
• [Presentation] Neuropathic pain mechanisms : TRP family and signal transduction molecules. (2008)
  • Author(s): Noguchi, K.
  • Organizer: NeuPSIG satellite to the Glasgow 2008 World Congress on Pain
  • Place of Presentation: London
  • Year and Date: 2008-08-13
• [Presentation] Contribution of changes in signal transduction molecules in DRG and spinal cord to neuropathic pain. (2008)
  • Author(s): Noguchi, K.
  • Organizer: The 3rd Asian Pain Symposium
  • Place of Presentation: Fukuoka
  • Year and Date: 2008-07-18
• [Presentation] 痛み伝達の調節機構-TRPファミリ-分子とシグナル伝達-(特別講演) (2008)
  • Author(s): 野口光一
  • Organizer: 第22回日本ニューロモデュレーション学会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-18
• [Presentation] MAP kinase regulation of pain : peripheral, central and glial mechanisms. (Workshops) (2008)
  • Author(s): Noguchi, K.
  • Organizer: 12th World Congress on Pain
  • Place of Presentation: Glasgow, UK.
• [Presentation] Neuropathic pain mechanisms: TRP family and signal transduction molecules. (Plenary lecture) (2008)
  • Author(s): Noguchi, K.
  • Organizer: NeuPSIG satellite to the Glasgow 2008 World Congress on Pain
  • Place of Presentation: London, UK.
• [Presentation] Contribution of Changes in Signal Transduction Molecules in DRG and Spinal Cord to Neuropathic Pain. (Symposium) (2008)
  • Author(s): Noguchi, K.
  • Organizer: The 3rd Asian Pain Symposium
  • Place of Presentation: Fukuoka
• [Presentation] 疼痛伝達の分子メカニズムの解明 (2007)
  • Author(s): 野口 光一
  • Organizer: 第313回大阪大学神経科学懇話会
  • Place of Presentation: 大阪
  • Year and Date: 2007-12-22
• [Presentation] TRP channel family and cutaneous sensation (2007)
  • Author(s): 野口 光一
  • Organizer: 第17回国際痒みシンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2007-09-15
• [Presentation] Roles of ERK5 in spinal microglia and primary sensory neurons for neuropathic pain. (Symposium) (2007)
  • Author(s): Noguchi, K.
  • Organizer: 7th IBRO World Congress of Neuroscience
  • Place of Presentation: Melbourne, Australia
• [Presentation] Roles of extracellular signal-regulated protein kinase (ERK)5 in spinal microglia and primary sensory neurons for neuropathic pain. (Workshop) (2007)
  • Author(s): Noguchi, K.
  • Organizer: Second International Congress on Neuropathic Pain
  • Place of Presentation: Berlin, Germany
• [Presentation] 分子と痛み(1):シグナルと痛み-MAPKを中心として (2007)
  • Author(s): 野口 光一
  • Organizer: 第2回痛み研究者の集い
  • Place of Presentation: 京都
• [Presentation] Roles of ERK5 in spinal microglia and primary sensory neurons for neuropathic pain (2007)
  • Author(s): Noguchi, K
  • Organizer: 7th IBRO World Congress of Neuroscience
  • Place of Presentation: Melbourne
• [Presentation] Roles of extracellular signal-regulated protein kinase(ERK)5 in spinal microglia and primary sensory neurons for neuropathic pain (2007)
  • Author(s): Noguchi, K
  • Organizer: Second International Congress on Neuropathic Pain
  • Place of Presentation: Berlin
• [Presentation] ニューロパチックペインモデルのDRG及び脊髄における分子変化 (2007)
  • Author(s): 野口 光一
  • 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, 他
  • Total Pages: 354
  • Publisher: 南江堂