Elucidation of molecular mechanisms in pain-emotion system for chronic pain and applicatiopn of BDNF treatment

• Project/Area Number: 24593057
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Yamaguchi University
• Principal Investigator: ISHIKAWA Toshizo 山口大学, 医学(系)研究科(研究院), 教授 (90034991)
• Co-Investigator(Kenkyū-buntansha): NAKANISHI Osamu 九州歯科大学, 歯学部, 名誉教授 (50137345) ; KAKEDA Takahiro 川崎医療福祉大学, 医療福祉学部, 准教授 (60403664) ; YAMAMOTO Misa 山口大学, 大学院医学系研究科, 講師 (70379957) ; FURUKAWA Shoei 岐阜薬科大学, 薬学部, 教授 (90159129) ; IBUKI Takae 京都府立医科大学, 大学院医学研究科, 講師 (90232587) ; TOKUDA Nobuko 山口大学, 大学院医学系研究科, 教授 (70227578) ; ISHIKAWA Kouzou 北海道大学, 遺伝子病制御研究所, その他 (20624795) ; SUZUKI Hidenori 山口大学, 大学院医学系研究科, 助教 (30393432)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 慢性疼痛 / 気分障害 / 神経栄養因子 / pERK / カテコール化合物 / magnetic stimulation / 神経障害性疼痛 / 細胞機能 / 磁気治療 / 痛覚ー情動系 / シグナル変調 / 磁気刺激治療 / chronic pain / depression / BDNF / ERK

Outline of Final Research Achievements

Depression-like behavior is often complicated by chronic pain. However, little is known about neurotrophic factor(BDNF) mediated preventing effect on mood disorder in chronic pain and its molecular mechanisms. We aimed to investigate the effects of magnetic field stimulation(MFS) and 4-methycatechol(4-MC) based on brain-derived neurotrophic factor (BDNF)-mediated signaling and gene expression in chronic pain. Both MFS and 4-MC ameliorated chronic pain and pain-related negative emotion by normalizing the induction of BDNF . These results suggest that MFS and 4-MC may represent the additional strategies against chronic pain associated with depression.

Research Products

• [Journal Article] Neurotropin ameliorates chronic pain via induction of brain-derived neurotrophic factor. (2015)
  • Author(s): T. Ishikawa, S. Yasuda, S. Minoda, T. Ibuki, K. Fukuhara, Y. Iwanaga, T. Ariyoshi, H. Sasaki
  • Journal Title: Cell Mol Neurobiol Volume: 35 Issue: 2 Pages: 231-241
  • DOI: 10.1007/s10571-014-0118-x
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Imipramine ameliorates pain-related negative emotion via induction of brain-derived neurotrophic factor (2014)
  • Author(s): S Yasuda, M Yoshida, H Yamagata, Y Iwanaga, H Suenaga, K Ishikawa, M Nakano, S Okuyama, Y Furukawa, S Furukawa, T Ishikawa
  • Journal Title: Cell Mol Neurobiol Volume: 34 Issue: 8 Pages: 1199-1208
  • DOI: 10.1007/s10571-014-0097-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fatty acid binding protein 7 regulates phagocytosis and cytokine production in Kupffer cells during liver injury. (2014)
  • Author(s): Miyazaki, H., Sawada, T., Kiyohira, M., Yu, Z., Nakamura, K., Yasumoto, Y., Kagawa, Y., Ebrahimi, M., Islam, A., Sharifi, K., Kawamura, S., Kodama, T., Yamamoto, Y., Adachi, Y., Tokuda, N., Terai, S., Sakaida, I., Ishikawa, T. and Owada, Y.
  • Journal Title: Am J Pathol Volume: 184 Issue: 9 Pages: 2505-2515
  • DOI: 10.1016/j.ajpath.2014.05.015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Spinal Cord Ischemia/Injury (2014)
  • Author(s): T Ishikawa, H Suzuki, K Ishikawa, S Yasuda, T Matsui, M Yamamoto, T Kakeda, S Yamamoto, Y Owada, TL Yaksh
  • Journal Title: Current Pharmaceutical Design Volume: 20 Issue: 36 Pages: 5738-5743
  • DOI: 10.2174/1381612820666140204113252
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 4-Methylcatechol prevents Derangements of brain-derived neurotrophic factor and TrkB-related signaling in anterior cingulate cortex in chronic pain with depression-like behavior (2014)
  • Author(s): K Ishikawa, S Yasuda, K Fukuhara, Y Iwanaga, Y Ida, J Ishikawa, H Yamagata, M Ono, T Kakeda, T Ishikawa
  • Journal Title: Neuroreport Volume: 25(4)
  • Peer Reviewed
• [Journal Article] Distribution of Spinal Sensitization Evoked by Inflammatory Pain Using Local Spinal Cord Glucose Utilization Combined with 3H-Phorbol 12, 13-Dibutyrate Binding in Rats (2013)
  • Author(s): Yasuda Seiko, Ishikawa K, Nakanishi O,Ishikawa T（10人中9番目）
  • Journal Title: ISRN Pain Volume: 2013 Pages: 213-216
  • DOI: 10.1155/2013/340167
  • Peer Reviewed
• [Journal Article] Anti-interleukin-6 receptorantibody reduces neuropathic pain following spinal cord injury in mice (2013)
  • Author(s): T Murakami, T Kanchiku, H Suzuki, Y Imajyo, Y Yoshida, H Nomura, Dancui, T Ishikawa, E Ikeda, T Taguchi
  • Journal Title: Experimental and Therapeutic Medicine Volume: 6(5) Issue: 5 Pages: 1194-1198
  • DOI: 10.3892/etm.2013.1296
  • Peer Reviewed
• [Journal Article] Activation of Different Signals Identified with Glia Cells Contribute to the Progression of Hyperalgesia (2013)
  • Author(s): S Yamamoto, Y Kishishita, M Yoshida, D Miura, H Suzuki, K Ishikawa, H Miyazaki, J Nojima, M Yamamoto, T Ishikawa
  • Journal Title: Cell Mol Neurobiol Volume: 33
  • Peer Reviewed
• [Journal Article] Spinal cord injury 1. Basic Concepts of Pathophysiological Mechanisms (2013)
  • Author(s): Ishikawa T, Suzuki H,Ishikawa K,Yasuda S, Kakeda T
  • Journal Title: Current Pharmaceutical Design Volume: 38
  • Peer Reviewed
• [Journal Article] Intracerebroventricular 4-Methylcatechol (4-MC) Ameliorates Chronic Pain Associated with Depression-Like Behavior Via Induction of Brain-Derived Neurotrophic Factor (BDNF) (2012)
  • Author(s): K Fukuhara, K Ishikawa, S Yasuda, Y Kishishita, H-K Kim, T Kakeda, M Yamamoto, T Norii, T Ishikawa
  • Journal Title: Cell Mol Neurobiol Volume: 32 Pages: 971-977
  • Peer Reviewed
• [Journal Article] Cutaneous magnetic stimulation reduces rat chronic pain via activation of the supra-spinal descending Pathway (2012)
  • Author(s): S Shiiba, S Yamamoto, H Sasaki, M Nishi, K Ishikawa, S Yasuda, N Tokuda, O Nakanishi, T Ishikawa
  • Journal Title: Cell Mol Neurobiol Volume: 32 Pages: 245-253
  • Peer Reviewed
• [Journal Article] ラット神経障害性疼痛に対する４-Methylcatecholの効果―細胞内シグナルによる評価 (2012)
  • Author(s): 松本吉洋, 石川浩三, 福原佳世子, 安田聖子, 吉田充広, 仲西 修, 石川敏三
  • Journal Title: 日本歯科麻酔学会誌 Volume: 40(1) Pages: 7-14
  • Peer Reviewed
• [Presentation] NeurotropinR) ameliorates depression-like behavior in chronie pain via induction of brain-derived neurotrophic factor, (2014)
  • Author(s): T Ishikawa, S Yasuda, H Fujimura, K Fukuhara, K Ishikawa, Y Ida, Y Iwanaga, T Ibuki
  • Organizer: NEUROSCIENCE
  • Place of Presentation: Washington, DC（ＵＳＡ）
  • Year and Date: 2014-11-16
• [Presentation] ow dose of imipramine ameliorates pain-related negative emotion via induction of brain-derived neurotrophic factor (2014)
  • Author(s): S Yasuda, H Yamagata, K Fukuhara, Y Iwanaga, M Nakano, K Ishikawa, Y Furukawa, Y Watanabe, T Ishikawa
  • Organizer: NEUROSCIENCE
  • Place of Presentation: Washington, DC（ＵＳＡ）
  • Year and Date: 2014-11-16
• [Presentation] 4-Methylcatechol, an inducer of brain derived neurotrophic factor, ameliorates pain-related negative emotion by preventing the ERK/CREB signaling pathway anterior cingulated cortex (2014)
  • Author(s): Y Iwanaga, K Fukuhara, S Yasuda, Y Ariyoshi, T Ibuki, S Okuyama, Y Furukawa, J Ishikawa, T Ishikawa
  • Organizer: NEUROSCIENCE
  • Place of Presentation: Washington, DC（ＵＳＡ）
  • Year and Date: 2014-11-16
• [Presentation] Angel TouchR）は前帯状回の神経栄養因子増加作用を介し痛覚―情動系障害を改善する, (2014)
  • Author(s): 山本 悟, 佐々木宏典, 石川浩三, 西 光晴, 安田聖子, 園田俊司, 三浦大輔, 石川敏三
  • Organizer: 第36回日本疼痛学会
  • Place of Presentation: KKRホテル大阪（大阪市）
  • Year and Date: 2014-06-21
• [Presentation] 抗うつ薬Imipramine のラット慢性疼痛における気分障害改善と神経栄養因子（BDNF）誘導作用 (2014)
  • Author(s): 安田聖子, 岩永泰武, 藤村博和, 吉田充広, 福原佳世子, 石川敏三
  • Organizer: 第36回日本疼痛学会
  • Place of Presentation: KKRホテル大阪（大阪市）
  • Year and Date: 2014-06-21
• [Presentation] ノイロトロピンR) の痛覚―情動系機能障害改善効果：脳由来神経栄養因子（BDNF）誘導作用 (2014)
  • Author(s): 石川敏三, 安田聖子, 石川浩三, 藤村博和, 井田唯香, 岩永泰武, 吉田充宏
  • Organizer: 第36回日本疼痛学会
  • Place of Presentation: KKRホテル大阪（大阪市）
  • Year and Date: 2014-06-21
• [Presentation] 4-Methylcatechol ameliorates chronic pain concurrent with mood disorder by inducing brain-derived neurotro-phic factor (2012)
  • Author(s): T Ishikawa, K Ishikawa, S Yasuda, Y Kishishita, A Masuzawa
  • Organizer: American Pain Society 31st
  • Place of Presentation: Honolulu Convention Center（Hawaii, USA）
• [Presentation] ラット慢性疼痛誘発情動障害の分子機構および神経栄養因子治療 (2012)
  • Author(s): 福原佳世子, 石川浩三, 安田聖子, 井田唯香, 掛田崇寛, 石川敏三
  • Organizer: 第34回日本疼痛学会
  • Place of Presentation: 熊本市国際交流会館（熊本）
• [Presentation] 慢性疼痛に併発する気分障害の分子機構解析：MonoamineとBDNF相互作用 (2012)
  • Author(s): 安田聖子, 石川浩三, 井田唯香, 増澤あゆみ, 福原佳世子, 石川敏三
  • Organizer: 第34回日本疼痛学会
  • Place of Presentation: 熊本市国際交流会館(熊本)
• [Presentation] Different activation of trkB-pERK contribute to the progression of hyperalgesia (2012)
  • Author(s): Y Kishishita, S Yasuda, S Yamamoto, D Miura, H Miyazaki, H Sasaki, T Ariyashi, K Ishikawa, Y Ida, T Ishikawa
  • Organizer: NEUROSCIENCE
  • Place of Presentation: New Orleans Convention Center(Louisana, USA)
• [Presentation] 4-Methylcathechol, neurotorophin inducer, prevents abnormal pain-emotion response including hypersensitization and mood disorder in rat with chronic pain (2012)
  • Author(s): M Yoshida, S Yasuda, S Minoda, K Ishikawa, S Yamamoto, Y Kishishita, S Watanabe, O Nakanishi, T Ishikawa
  • Organizer: NEUROSCIENCE
  • Place of Presentation: New Orleans Convention Center(Louisana, USA)
• [Presentation] 4- Methylcathechol (4-MC) modulates pehronic pain with depression via. Prevention of abnormal pERK and BDNF in rats (2012)
  • Author(s): Y Iwanaga, K Ishikawa, K Fukuhara, Y Kishishita, M Yamamoto, D Miura, K Okano, Y Watanabe, T Ishikawa
  • Organizer: NEUROSCIENCE
  • Place of Presentation: Orleans Convention Center(Louisana, USA)
• [Presentation] 4-MCの神経保護効果のおけるTrkB受容体関連―シグナル変調の抑止作用
  • Author(s): 福原佳世子, 岩永泰武, 石川浩三, 安田聖子, 掛田崇寛, 石川敏三
  • Organizer: 第35回日本疼痛学会
  • Place of Presentation: 大宮ソニックシティ（埼玉県さいたま市）
• [Presentation] Activation of Descending Inhibitory System May Prevent Chronic Pain Related Depression: Possible Interaction Between 5-HT and Brain-Derived Neurophic Factor
  • Author(s): T Ishikawa, S Yasuda, K Ishikawa，T Kakeda, M Yanagihara
  • Organizer: 8th Congress of the European Federation of IASP(R) Chapters (EFIC(R)) ; PAIN IN EUROPE VIII
  • Place of Presentation: Florence, Italy, Firenze Fiera S.p.A., Congress & Exhibition Center
• [Presentation] 4-Methylcatechol (4-MC), BDNF Inducer, Ameliorates Chronic Pain with Depression via. Prevention of TrkB Related Signaling
  • Author(s): O Nakanishi, K Ishikawa, K Fukuhara, S Yasuda, M Yoshida, T Ishikawa
  • Organizer: 8th Congress of the European Federation of IASP(R) Chapters (EFIC(R)) ; PAIN IN EUROPE VIII
  • Place of Presentation: Florence, Italy, Firenze Fiera S.p.A., Congress & Exhibition Center
• [Presentation] Neuroprotective effects of 4-methylcatechol against depression related to chronic pain: similar action to trkb agonist,7, 8, 3’- thf
  • Author(s): T Ishikawa, Y Iwanaga, K Ishikawa, S Yasuda, Y Ida, K Fukuhara, M Ono, M Yamamoto
  • Organizer: NEUROSCIENCE 2013
  • Place of Presentation: San Diego, USA
• [Presentation] Reconfirmation of interaction between monoaminergic neuron and BDNF in RVM with Lmipramine for reducing depression related to chronic pain
  • Author(s): S Yasuda, T Kakeda, Y Ida, H Yamagata, Y Iwanaga, S Sonoda, H Suzuki, T Ibuki, T Ishikawa
  • Organizer: NEUROSCIENCE 2013
  • Place of Presentation: San Diego, USA
• [Presentation] Spinal microglia mediate the modulation in the GABAA receptor antagonist induced allodynia
  • Author(s): M Yoshida, O Nakanishi, K Ishikawa, D Miura, H Sasaki, S Yasuda, Y Ida, Y Iwanaga, S Watanabe, T Ishikawa
  • Organizer: NEUROSCIENCE 2013
  • Place of Presentation: San Diego, USA