Ionic channel expression in primary afferent Aβ fibers:analysis of regulatory mechanism and therapeutic application to chronic pain

• Project/Area Number: 18613003
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pain science
• Research Institution: Kanazawa University
• Principal Investigator: YOKOYAMA Shigeru Kanazawa University, Graduate School of Medicine, Associate Professor (00210633)
• Co-Investigator(Kenkyū-buntansha): HIGASHIDA Haruhiro Kanazawa University, Graduate School of Medicine, Professor (30093066) ; IKEDA Kazuo Kanazawa University, University Hospital, Lecturer (60231130)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,050,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2006: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: ionic channel / nerve injury / Pain / sensory neuron / 脊髄後退神経節ニューロン

Research Abstract

Altered ionic channel expression and sympathetic nerve sprouting have been thought to underlie a condition of chronic pain, such as complex regional pain syndrome. Following a few weeks after injury, postganglionic sympathetic nerve endings sprout and surround cell bodies of dorsal root ganglion (DRG) neurons, and make abnormal synaptic contacts. Aberrant interactions between sensory and sympathetic neurons are also located in the peripheral sites including neuroma at a transected nerve and intradermal region. Despite extensive studies, however, little is known about the molecules that promote the outgrowth of sympathetic nerve. To identify chronic pain-associated proteins, we screened a subtractive cDNA library enriched for mRNAs increased in the proximal stump of transected rat sciatic nerve. Among the identified proteins, collagen type VI was induced prominently in the proximal stump. Collagen type VI-coated plastic plate allowed robust neurite outgrowth of dorsal root and superior cervical ganglion neurons dissociated from adult rats, NSC34 spinal motor neuron-like cells, and PC12 pheochromocytoma cells. The neurite-promoting effect was more long-lasting than those in collagen type I-, laminin-, poly-D-ornithine-, and poly-L-lysine-coated plates. In addition, coating with collagen type VI prevented death of PC12 and NSC34 cells to the extent comparable to laminin. Immunohistochemical analysis of damaged sciatic nerve revealed that intense immunoreactivity for collagen type VI was localized in nonmyelinating Schwann cells, macrophages and fibroblasts, and along vessels and tyrosine hydroxylase (TM-positive nerve fibers. These results suggest that collagen type VI promotes not only regeneration of motor and somatosensory nerves, but also sprouting of sympathetic nerve. We are planning to examine whether somatosensory and /or sympathetic neurons in contact with collagen type VI alter expression levels of ionic channels.

Research Products

• [Journal Article] Quantitative regional blood-flow measurements in exercising skeletal muscle based on 99mTC-pertechnetate clearance. (2008)
  • Author(s): Seto, M., et. al.
  • Journal Title: Nucl. Med. Commun. (掲載確定)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system. (2007)
  • Author(s): Higashida, H., et. al.
  • Journal Title: Neurochem. Int. 51 Pages: 192-199
  • NAID: 120001141007
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Oxytocin released from mouse hypothalamus and nerve endings by extracellular application of beta-NAD^+ and cyclic ADP ribose. (2007)
  • Author(s): Jin, D., et. al.
  • Journal Title: Nat. Protocols DOI:10.1308/nprot2007.214電子論文
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] CD38 is critical for social behaviour by regulating oxytocin secretion. (2007)
  • Author(s): Jin, D., et. al.
  • Journal Title: Nature 446 Pages: 41-45
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Overexpression of constitutively active form of CD38/ADP-ribosyl cyclase enhances acetylcholine-induced M(KCNQ)-current inhibition in rodent NG108-15 neuroblastoma cells. (2007)
  • Author(s): Higashida, H., et. al.
  • Journal Title: Neurosci. Res. 57 Pages: 339-346
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Bradykinin activates ADP-ribosyl cyclase in neuroblastoma cells:Intracellular concentration decrease in NAD and increase in cyclic ADP-ribose. (2007)
  • Author(s): Higashida, H., et. al.
  • Journal Title: FEBS Letters 446 Pages: 41-45
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system (2007)
  • Author(s): Higashida, H., Salmina, A., B., Olovyannikova, R., Hashii, M., Yokovama, S., Koizumi, K., Jin, D., Liu, H., X., Lopatina, O., Amita, S., Islam, S. Md., Jun, H., J., Noda, M
  • Journal Title: Neurochem. Int 51 Pages: 192-199
  • NAID: 120001141007
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Oxytocin released from mouse hypothalamus and nerve endings by extracellular application of beta-NAD^+ and cyclic ADP ribose (2007)
  • Author(s): Jin, D., Liu, X., X., Lopatina, O., Hashii, M., Yokovama, S., Koizumi, K., Amina, S., Shuto, S., Shiraishi, Y, Tanaka, S., Higashida, H
  • Journal Title: Nat. Protocols. (Protocols Network) DOI : 10.1038/nprot.2007 Pages: 214-214
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CD38 is critical for social behavior by regulating oxytocin secretion (2007)
  • Author(s): Jin, D., Liu, H.-X., Hirai, H., Torashima, T., Nagai, T., Lopatina, O., Schayder, N., Yamada, K., Noda, M., Seike, T., Fujita, K., Takasawa, S., Yokovama, S., Koizumi, K., Shiraishi, M., Tanaka, S., Hashii, M., Yoshihara, T., Higashida, K., Islam, Md., Yamada, N., Hayashi, K., Noguchi, N., Kato, I., Okamoto, H., Matsushima, A., Salmina, A., Munesue, T., Shimizu, N., Mochida, S., Asano, M., Higashida, H
  • Journal Title: Nature 446 Pages: 41-45
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of constitutively active form of human CD38/ADP-ribosyl cyclase enhances acetylcholine-induced M(KCNQ) -current inhibition in rodent NG108-15 neuroblastoma cells (2007)
  • Author(s): Higashida, H., Bowden, S., E., H., Yokovama. S., Egorova, A., Hashii, M., Hoshi, N., Zhang, J.-S., Knijnik, R., Noda, M., Zhong, Z.-G., Takeda, H., Akita, T., Kuba, K., Yamagishi, S., Shimizu, N., Takasawa, S., Okamoto, H., Robbins, J
  • Journal Title: Neurosci. Res 57 Pages: 339-346
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system (2007)
  • Author(s): Higashida, H., et. al.
  • Journal Title: Neurochem.Int. 51 Pages: 192-199
  • NAID: 120001141007
  • Peer Reviewed
• [Journal Article] CD38 is critical for social behaviour by regulating oxytocin secretion (2007)
  • Author(s): Duo Jin, et al.
  • Journal Title: Nature 446 Pages: 41-45
• [Journal Article] 膜電位依存性イオンチャンネルの分子構造、多様性と神経機能調節 (2007)
  • Author(s): 横山 茂
  • Journal Title: 金沢大学十全医学会誌 115 Pages: 130-133
• [Journal Article] Bradykinin activates ADP-ribosyl cyclase in neuroblastoma cells : intracellular concentration decrease in NAD and increase in cyclic ADP-ribose (2006)
  • Author(s): Higashida, H., Salmina, A., Hashii, M., Yokovama, S., Zhang, J.-S., Noda, M., Zhong, Z.-H., Jin, D
  • Journal Title: FEBS Lett 580 Pages: 4857-6850
  • NAID: 120000809376
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bradykinin activates ADP-ribosyl cyclase in neuroblastoma cells : Intracellular concentration decrease in NAD and increase in cyclic ADP-ribose. (2006)
  • Author(s): Haruhiro Higashida, et al.
  • Journal Title: FEBS Letters 580 Pages: 4857-4860
  • NAID: 120000809376
• [Journal Article] Quantitative regional blood-flow measurements in exercising skeletal muscle based on^99mTc-pertechnetate clearance
  • Author(s): Seto, M., Bunko, H., Shuke, N., Takahashi, K., Sakaibori, Y., Terada, H., Imabayashi, E., Kuji, I., Matsuda, H., Yokovama, S
  • Journal Title: Nucl. Med. Commun (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Social memory, mental care and oxytocin secretion, but not vasopressin release, require CD38 in mice
  • Author(s): Higashida, H., Jin, D., Liu, H.-X., Lopatina, O., Yokovama, S., Koizumi, K., Hashii, M., Islam, S., Md., Hayashi, K., Munesue, T
  • Journal Title: In : Neurobiology of the Parental Mind, Academic Press (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Quantitative regional blood-flow measurements in exercising skeletalmuscle based on ^<99>Tc-pertechnetate clearance
  • Author(s): Seto, M., et. al.
  • Journal Title: Nucl.Med.Commun.
  • Peer Reviewed
• [Presentation] Genetic analysis of peripheral nerve regeneration. (2007)
  • Author(s): Yokoyama, S.
  • Organizer: Korea-Japan Symposium on Recent Advance in Medical Science
  • Place of Presentation: Chonbuk National University Medical School, Korea
  • Year and Date: 2007-11-15
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Genetic analysis of peripheral nerve regeneration (2007)
  • Author(s): Yokovama, S
  • Organizer: Korea-Japan Symposium on Recent Advance in Medical Science
  • Place of Presentation: Chonbuk National University Medical School. Jeonju, Korea
  • Year and Date: 2007-11-15
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Genetic analysis of peripheral nerve regeneration (2007)
  • Author(s): Yokoyama, S.
  • Organizer: Korea-Japan Symposium on Recent Advance in Medical Science
  • Place of Presentation: Chonbuk National University Medical School, Korea
  • Year and Date: 2007-11-15
• [Presentation] Upregulation of collagen type VI in the axotomized rat sciatic nerve. (2007)
  • Author(s): Yokoyama, S.
  • Organizer: The 38th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, CA, U. S. A.
  • Year and Date: 2007-11-07
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Upregulation of collagen type VI in the axotomized rat sciatic nerve (2007)
  • Author(s): Yokovama, S., Hinoki, S., Ikeda K., Tomita, K., Higashida, H
  • Organizer: The 38th Annual Meeting of Scociety for Neuroscience
  • Place of Presentation: San Diego, CA, U.S.A
  • Year and Date: 2007-11-07
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Upregulation of collagen type VI in the axotomized rat sciatic nerve (2007)
  • Author(s): Yokoyama, S.
  • Organizer: The 38th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, CA, U.S.A.
  • Year and Date: 2007-11-07
• [Presentation] Trial of social behavior tests in ordinal house mice (2007)
  • Author(s): Jin, D., Liu, H.-X., Hashii, M., Yokovama, S., Koizumi, K., Lopatina, O., Islam, S., Md., Higashida, H
  • Organizer: The 49th Annual Meeting of the Japanese Society for Neurochemistry
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2007-09-15
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] ADP-ribosyl cyclase activity and oxytocin levels in mouse maternal behavior. (2007)
  • Author(s): Lopatina, O., et. al.
  • Organizer: 第50回日本神経化学会大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-09-12
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] ADP-ribosyl cyclase activity and oxytocin levels in mouse maternal behavior (2007)
  • Author(s): Lopatina, O., Koizumi, K., Schnayder, N., Liu, H.-X., Jin, D., Yokovama, S., Hashii, M., Islam, S., Md., Amina, S., Higashida, H
  • Organizer: The 50th Annual Meeting of the Japanese Society for Neurochemistry
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2007-09-12
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] ADP-ribosyl cyclase activity and oxytocin levels in mouse matemal behavior (2007)
  • Author(s): Lopatina, O., et. al.
  • Organizer: 第50回日本神経化学会大会
  • Place of Presentation: パシフイコ横浜
  • Year and Date: 2007-09-12
• [Presentation] 神経再生遺伝子 -β6-, β7-tubulin遺伝子の発現解析 (2007)
  • Author(s): 古田拓也、横山 茂
  • Organizer: 第4回脳細胞・発達・学習・記憶分子シンポジウム 革新脳科学COE・金沢大学十全医学会・脳医科学専攻合同シンポジウム
  • Place of Presentation: 金沢大学医学部記念館
  • Year and Date: 2007-09-08
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Genes associated with nerve regeneration : expression analysis of β6- and β7-tubulin genes (2007)
  • Author(s): Furuta, T., Yokovama, S
  • Organizer: The 4th Symposium on Brain Cell, Development, Learning, and Memory
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 2007-09-08
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 神経再生遺伝子-β6-,β7-tubulin遺伝子の発現解析 (2007)
  • Author(s): 古田 拓也、横山 茂
  • Organizer: 第4回脳細胞・発達・学習・記憶分子シンポジウム革新脳科学COE・金沢大学十全医学会・脳医科学専攻合同シンポジウム
  • Place of Presentation: 金沢大学医学部記念館
  • Year and Date: 2007-09-08
• [Presentation] 末梢神経を用いた再生・発達関連遺伝子の探索 (2007)
  • Author(s): 横山 茂
  • Organizer: 第4回脳細胞・発達・学習・記憶分子シンポジウム 革新脳科学COE・金沢大学十全医学会・脳医科学専攻合同シンポジウム
  • Place of Presentation: 金沢大学医学部記念館
  • Year and Date: 2007-09-07
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 末梢神経を用いた再生・発達関連遺伝子の探索 (2007)
  • Author(s): 横山 茂
  • Organizer: 第4回脳細胞・発達・学習・記憶分子シンポジウム革新脳科学COE・金沢大学十全医学会・脳医科学専攻合同シンポジゥム
  • Place of Presentation: 金沢大学医学部記念館
  • Year and Date: 2007-09-07
• [Presentation] 神経損傷部位で発現誘導される遺伝子群の探索 (2007)
  • Author(s): 横山 茂
  • Organizer: 平成18年度金沢大学重点経費シンポジウム「損傷中枢神経の再生」
  • Place of Presentation: 金沢大学医学部記念館
  • Year and Date: 2007-02-09
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Exploration of genes induced in injured nerve (2007)
  • Author(s): Yokovama, S
  • Organizer: Symposium on Regeneration of Injured Central nervous system (COE research program of Kanazawa University)
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 2007-02-09
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Exploration of regeneration- and development-associated genes in peripheral nerve (2007)
  • Author(s): Yokovama., S
  • Organizer: The 4th Symposium on Brain Cell (Development) (Learning) (Memory)
  • Place of Presentation: Kanazawa, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 軸索損傷後の末梢神経で誘導される遺伝子群の探索 (2006)
  • Author(s): 横山 茂
  • Organizer: 第53回中部日本生理学会
  • Place of Presentation: 山梨大学教育人間科学部
  • Year and Date: 2006-09-28
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Exploration of genes induced in axotomized peripheral nerve (2006)
  • Author(s): Yokovama, S
  • Organizer: The 53th Meeting of Physiological Society of
  • Place of Presentation: Kofu, Japan
  • Year and Date: 2006-09-28
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 索損傷後の末梢神経で誘導される遺伝子群の探索 (2006)
  • Author(s): 横山 茂
  • Organizer: 第4回脳細胞・発達・学習・記憶分子シンポジウム 革新脳科学COE・金沢大学十全医学会・脳医科学専攻合同シンポジウム
  • Place of Presentation: 金沢大学医学部記念館
  • Year and Date: 2006-09-23
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Exploration of genes induced in axotomized peripheral nerve (2006)
  • Author(s): Yokovama, S
  • Organizer: The 3rd Symposium on Brain Cell (Development) (Learning) (Memory)
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 2006-09-23
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Trial of social behavior tests in ordinal house mice. (2006)
  • Author(s): Jin, D., et. al.
  • Organizer: 第49回日本神経化学会大会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2006-09-15
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 培養ラットシュワン細胞におけるインターロイキン6(IL-6)による末梢ミエリン蛋白22(PMP22)mRNAの発現誘導 (2006)
  • Author(s): 伊藤 貴明, 他
  • Organizer: 第21回日本整形外科学会基礎学術集会
  • Place of Presentation: 長崎
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Induction of peripheral myelin protein 22 (PMP22) by interleukin-6 (IL-6) in cultured rat Schwann cells (2006)
  • Author(s): Ito, T., Ikeda, K., Tomita, K., Higashida, H., Yokovama, S
  • Organizer: The 21th Academic Meeting of the Japanese Orthopaedic Association
  • Place of Presentation: Nagasaki, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Social memory, mental care and oxytocin, but not vasopressin release, require CD38 in mice. In: Neurobiology of the Parental Mind. (2008)
  • Author(s): Higashida, H., et. al.
  • Total Pages: 15
  • Publisher: Academic Press
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Social memory, mental care and oxytocin, but not vasopressin release ,repuire CD38 in mice. In: Neurobiology of the Parental Mind
  • Author(s): Higashida, H., et. al.
  • Total Pages: 15
  • Publisher: Academic Press