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Molecular mechanism of chronic pain via histone-dependent peripheral sensitization

Research Project

Project/Area Number 24592356
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Anesthesiology/Resuscitation studies
Research InstitutionWakayama Medical University

Principal Investigator

KIGUCHI Norikazu  和歌山県立医科大学, 医学部, 講師 (90433341)

Co-Investigator(Kenkyū-buntansha) KISHIOKA Shiroh  和歌山県立医科大学, 医学部, 教授 (60137255)
KOBAYASHI Yuka  和歌山県立医科大学, 医学部, 助教 (20511562)
FUKAZAWA Yohji  関西医療大学, 保健医療学部, 准教授 (70336882)
Research Collaborator SAKAGUCHI Haruka  
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords慢性疼痛 / 神経障害性疼痛 / ヒストン / マクロファージ / ケモカイン / エピジェネティクス / 炎症 / サイトカイン / CCL3 / フェノタイプ / CCL8 / MIP / VEGF
Outline of Final Research Achievements

We focused on the roles of histone, a nuclear protein, in molecular mechanisms of chronic pain. Immune cells including macrophages were accumulated in the injured nerves, and they produced pain-facilitating molecules such as chemokines. We found that these expressions were mediated by modification (acetylation and methylation) of histones. Moreover, macrophages were polarized into pain-facilitating phenotype by histone modification. We demonstrated that inhibition of these types of macrophages by pharmacological treatment was able to improve chronic pain. Taken together, histone modification in macrophages might be key machinery of chronic pain, and it will be candidate of novel therapeutic target.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (35 results)

All 2015 2014 2013 2012 Other

All Journal Article (13 results) (of which Peer Reviewed: 12 results,  Open Access: 2 results,  Acknowledgement Compliant: 1 results) Presentation (19 results) (of which Invited: 4 results) Remarks (3 results)

  • [Journal Article] Peripheral alpha4beta2 nicotinic acetylcholine receptor signalling attenuates tactile allodynia and thermal hyperalgesia after nerve injury in mice.2015

    • Author(s)
      Saika F, Kiguchi N, Kobayashi Y, Kishioka S
    • Journal Title

      Acta Physiol (Oxf)

      Volume: 213(2) Issue: 2 Pages: 462-71

    • DOI

      10.1111/apha.12437

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain.2015

    • Author(s)
      Kiguchi N, Kobayashi Y, Saika F, Sakaguchi H, Maeda T, Kishioka S
    • Journal Title

      Pain

      Volume: 156(4) Issue: 4 Pages: 684-93

    • DOI

      10.1097/j.pain.0000000000000097

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Epigenetic regulation of CC-chemokine ligand 2 in nonresolving inflammation.2014

    • Author(s)
      Kiguchi N, Saika F, Kobayashi Y, Kishioka S
    • Journal Title

      Biomol Concepts

      Volume: 5(4) Issue: 4 Pages: 265-73

    • DOI

      10.1515/bmc-2014-0022

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Vascular endothelial growth factor signaling in injured nerves underlies peripheral sensitization in neuropathic pain.2014

    • Author(s)
      Kiguchi N, Kobayashi Y, Kadowaki Y, Fukazawa Y, Saika F, Kishioka S
    • Journal Title

      J Neurochem

      Volume: 129 Issue: 1 Pages: 169-178

    • DOI

      10.1111/jnc.12614

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] 傷害末梢神経におけるヒストン修飾は神経障害性疼痛を調節する.2014

    • Author(s)
      木口倫一、岸岡史郎
    • Journal Title

      Pain Research

      Volume: 29 Pages: 9-16

    • NAID

      130004839642

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Epigenetic upregulation of CCL2 and CCL3 via histone modifications in infiltrating macrophages after peripheral nerve injury.2013

    • Author(s)
      Kiguchi N, Kobayashi Y, Saika F, Kishioka S
    • Journal Title

      Cytokine

      Volume: 64 Issue: 3 Pages: 666-672

    • DOI

      10.1016/j.cyto.2013.09.019

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pharmacokinetic evidence for the long-lasting effect of nor-binaltorphimine, a potent kappa opioid receptor antagonist, in mice.2013

    • Author(s)
      Kishioka S, Kiguchi N, Kobayashi Y, Yamamoto C, Saika F, Wakida N, Ko MC, Woods JH
    • Journal Title

      Neurosci Lett

      Volume: 552 Pages: 98-102

    • DOI

      10.1016/j.neulet.2013.07.040

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Epigenetic augmentation of the macrophage inflammatory protein 2/C-X-C chemokine receptor type 2 axis through histone H3 acetylation in injured peripheral nerves elicits neuropathic pain2012

    • Author(s)
      Kiguchi N, et al
    • Journal Title

      J Pharmacol Exp Ther

      Volume: 340 Issue: 3 Pages: 577-587

    • DOI

      10.1124/jpet.111.187724

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] CC-chemokine ligand 4/macrophage inflammatory protein-1β participates in the induction of neuropathic pain after peripheral nerve injury.2012

    • Author(s)
      Saika F, Kiguchi N, Kobayashi Y, Fukazawa Y, and Kishioka S
    • Journal Title

      Eur J Pain.

      Volume: 16 Issue: 9 Pages: 1271-1280

    • DOI

      10.1002/j.1532-2149.2012.00146.x

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Chemokines and cytokines in neuroinflammation leading to neuropathic pain2012

    • Author(s)
      Kiguchi N, et al
    • Journal Title

      Curr Opin Pharmacol

      Volume: 12(invited) Issue: 1 Pages: 55-61

    • DOI

      10.1016/j.coph.2011.10.007

    • Related Report
      2012 Research-status Report
  • [Journal Article] Activation of nicotinic acetylcholine receptors on bone marrow-derived cells relieves neuropathic pain accompanied by peripheral neuroinflamation.2012

    • Author(s)
      Kiguchi N, Kobayashi Y, Maeda T, Tominaga S, Nakamura J, Fukazawa Y, Ozaki M and Kishioka S
    • Journal Title

      Neurochem Int.

      Volume: 61 Issue: 7 Pages: 1212-1219

    • DOI

      10.1016/j.neuint.2012.09.001

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] The critical role of spinal ceramide in the development of partial sciatic nerve ligation-induced neuropathic pain in mice2012

    • Author(s)
      Kobayashi Y, Kiguchi N, Maeda T, Ozaki M, Kishioka S.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 421 Issue: 2 Pages: 318-322

    • DOI

      10.1016/j.bbrc.2012.03.153

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Inhibition of morphine tolerance is mediated by painful stimuli via central mechanisms2012

    • Author(s)
      Iwai S, Kiguchi N, Kobayashi Y, Fukazawa Y, Saika F, Ueno K, Yamamoto C, Kishioka S
    • Journal Title

      Drug Discov Ther

      Volume: 6 Pages: 31-37

    • NAID

      130005054734

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] IL-13 はマクロファージのフェノタイプシフトによって神経障害性疼痛を緩和する2015

    • Author(s)
      阪口晴香、木口倫一、小林悠佳、雑賀史浩、岸岡史郎
    • Organizer
      第88回日本薬理学会年会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] 末梢免疫細胞を標的とした神経障害性疼痛病態の解明2015

    • Author(s)
      小林悠佳、木口倫一、深澤洋滋、雑賀史浩、前田武彦、岸岡史郎
    • Organizer
      第88回日本薬理学会年会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-20
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] IL-13は末梢神経傷害時の炎症性マクロファージを抑制する2014

    • Author(s)
      阪口晴香、木口倫一、小林悠佳、雑賀史浩、岸岡史郎
    • Organizer
      第126回日本薬理学会近畿部会
    • Place of Presentation
      和歌山
    • Year and Date
      2014-10-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] マクロファージを標的とした神経障害性疼痛治療戦略の検討2014

    • Author(s)
      木口倫一、小林悠佳、雑賀史浩、岸岡史郎
    • Organizer
      第34回鎮痛薬・オピオイドペプチドシンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2014-09-06
    • Related Report
      2014 Annual Research Report
  • [Presentation] Peripheral macrophages in long-lasting neuroinflammation and neuropathic pain.2014

    • Author(s)
      Kiguchi N, Kishioka S
    • Organizer
      生体機能と創薬シンポジウム2014
    • Place of Presentation
      大阪
    • Year and Date
      2014-08-29
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] IL-4はマクロファージの機能調節を介して神経障害性疼痛を改善する2014

    • Author(s)
      木口倫一、小林悠佳、岸岡史郎
    • Organizer
      第36回日本疼痛学会
    • Place of Presentation
      大阪
    • Year and Date
      2014-06-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] 傷害末梢神経におけるヒストン修飾は神経障害性疼痛を調節する

    • Author(s)
      木口倫一、岸岡史郎
    • Organizer
      第35回日本疼痛学会
    • Place of Presentation
      さいたま
    • Related Report
      2013 Research-status Report
  • [Presentation] 神経障害性疼痛における末梢性VEGFシグナルの関与

    • Author(s)
      木口倫一、小林悠佳、門脇友維、雑賀史浩、岸岡史郎
    • Organizer
      第33回鎮痛薬・オピオイドペプチドシンポジウム
    • Place of Presentation
      神戸
    • Related Report
      2013 Research-status Report
  • [Presentation] 神経炎症を標的とした神経障害性疼痛の末梢性調節

    • Author(s)
      木口倫一、小林悠佳、雑賀史浩、岸岡史郎
    • Organizer
      第2回ニューロカンファレンス和歌山
    • Place of Presentation
      和歌山
    • Related Report
      2013 Research-status Report
  • [Presentation] IL-4は炎症性マクロファージおよび神経障害性疼痛を抑制する

    • Author(s)
      木口倫一、小林悠佳、雑賀史浩、前田武彦、岸岡史郎
    • Organizer
      第87回日本薬理学会年会
    • Place of Presentation
      仙台
    • Related Report
      2013 Research-status Report
  • [Presentation] 神経障害性疼痛治療標的としての末梢ニコチン性アセチルコリン受容体

    • Author(s)
      岸岡史郎、木口倫一、雑賀史浩、小林悠佳
    • Organizer
      第87回日本薬理学会年会
    • Place of Presentation
      仙台
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] 骨髄由来細胞におけるニコチン性アセチルコリン受容体シグナルは神経障害性疼痛を改善する

    • Author(s)
      木口倫一、小林悠佳、前田武彦、冨永信太、中村淳、岸岡史郎
    • Organizer
      第121回日本薬理学会近畿部会
    • Place of Presentation
      徳島
    • Related Report
      2012 Research-status Report
  • [Presentation] Epigenetic Augmentation of the Macrophage Inflammatory Protein 2/C-X-C Chemokine Receptor Type 2 Axis through Histone H3 Acetylation in Injured Peripheral Nerves Elicits Neuropathic Pain

    • Author(s)
      木口倫一
    • Organizer
      第80回和歌山医学会総会
    • Place of Presentation
      和歌山
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] マクロファージ炎症性タンパク質は末梢神経炎症を介して神経障害性疼痛を惹起する

    • Author(s)
      木口倫一、岸岡史郎
    • Organizer
      第34回日本疼痛学会
    • Place of Presentation
      熊本
    • Related Report
      2012 Research-status Report
  • [Presentation] 骨髄由来細胞におけるニコチン性アセチルコリン受容体シグナルの神経障害性疼痛改善効果

    • Author(s)
      木口倫一、小林悠佳、前田武彦、岸岡史郎
    • Organizer
      第35回日本神経科学大会
    • Place of Presentation
      名古屋
    • Related Report
      2012 Research-status Report
  • [Presentation] Augmentation of the MIP-2/CXCR2 axis through histone H3 acetylation in injured peripheral nerves facilitates neuropathic pain

    • Author(s)
      Kiguchi N, Kobayashi Y, Kishioka S
    • Organizer
      Neuroscience 2012, SfN’s 42nd annual meeting
    • Place of Presentation
      New Orleans, LA, USA
    • Related Report
      2012 Research-status Report
  • [Presentation] ケモカインによる末梢感作と神経障害性疼痛

    • Author(s)
      木口倫一、小林悠佳、岸岡史郎
    • Organizer
      第1回ニューロカンファレンス和歌山
    • Place of Presentation
      和歌山
    • Related Report
      2012 Research-status Report
  • [Presentation] Macrophage inflammatory proteins contributing to neuropathic pain were upregulated by histone modifications after peripheral nerve injury

    • Author(s)
      Kiguchi N, Kobayashi Y, Kishioka S
    • Organizer
      International Symposium for Neurosciences 2013
    • Place of Presentation
      仙台
    • Related Report
      2012 Research-status Report
  • [Presentation] 血管新生マクロファージは末梢神経炎症を伴う神経障害性疼痛に関与する

    • Author(s)
      木口倫一、小林悠佳、岸岡史郎
    • Organizer
      第86回日本薬理学会年会
    • Place of Presentation
      福岡
    • Related Report
      2012 Research-status Report
  • [Remarks] 和歌山県立医科大学医学部薬理学教室

    • URL

      http://www.wakayama-med.ac.jp/dept/igakubu/160416/index.html

    • Related Report
      2014 Annual Research Report
  • [Remarks] 和歌山県立医科大学医学部 薬理学教室

    • URL

      http://www.wakayama-med.ac.jp/dept/igakubu/160416/index.html

    • Related Report
      2013 Research-status Report
  • [Remarks] 和歌山県立医科大学医学部薬理学教室

    • URL

      http://www.wakayama-med.ac.jp/dept/igakubu/160416/index.html

    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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