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Study on the molecular mechanisms for neuronal plasticicity in the drug dependence

Research Project

Project/Area Number 09470503
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

SATOH Masamchi  Kyoto University, Faculty of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (80025709)

Co-Investigator(Kenkyū-buntansha) NAKAGAWA Takayuki  Kyoto University, Faculty of Pharmaceutical Sciences, Instructor, 薬学研究科, 助手 (30303845)
MINAMI Masabumi  Kyoto University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学研究科, 助教授 (20243040)
SAJI Hideo  Kyoto University, Faculty of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (40115853)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 1998: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥10,500,000 (Direct Cost: ¥10,500,000)
Keywordsopioid / opioid receptor / opioid dependence / adenylyl cyclase / supersensitization / G-protein / RGS4 / slow depolarization / 脱感作 / RGS / 可塑的神経機能変化 / 禁断症状 / Ca^<2+>チャネル
Research Abstract

We investigated the molecular mechanism responsible for supersensitization of the AC system induced by sustained opioid treatment using CHO cells expressing one of the cloned opioid receptors. In cells treated for 4 h with opioid agonists, challenge with opioid antagonists induced supersensitization of the AC system over the naive level, but had no effect on GTPase activity. This phenomenon was not affected by cycloheximide. To examine the involvement of the interaction between G-protein and AC in the development of supersensitization, we used CHO cells co-expressing the opioid receptor and some chimeric G-protein alpha_<i2>/alpha_q subunits. Our results revealed that a specific region of which is responsible for the interaction with AC, is closely related. Furthermore, we observed that supersensitization is also induced by activation of PTX-insensitive G_z.
On the other hand, we examined the regulation of RGS (regulators of G-protein signaling) 4 mRNA, which has been reported to stimulate the GTPase activity of G-protein alpha subunits, in PC12 cells stably expressing cloned opioid receptors by northern blot analysis. Treatment with opioid agonists increased the expression of RGS4 mRNA with a peak at 1-4 h. The inductions of RGS4 mRNA were blocked by antagonists and pertussis toxin. Furthermore, expression of recombinant RGS4 protein in HEK293 cells suppressed the opioid receptor-mediated inhibtory effect on forskolin-stimulated cAMP accumulation.
In transverse slices with the dorsal root attached, which were prepared from the spinal cord of adult rats, the repetitive stimulation to excite C-fibers but not Adelta-fibers evoked slow depolarization (SD) of the substantia gelatinosa neuron in spinal cord. SD was not inhibited by activation of neither glutamate- nor tachykinin NK1-receptor. On the other hand, SD was inhibited by activation of presynaptic mu-opioid, GABA_A, GABA_B, and 5-HT_<1A> receptors.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Ozawa, T.et al.: "Supersensitization of the adenylyl cyclase system in chinese hamster ovary cells co-expressing cloned opioid receptors and G_z, a PTX-insensitive G-protein." Neurosci.Lett.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kaneko, S.et al.: "Inhibition of Ca^<2+> channel current by μ- and κ-opipid receptors coexpressed in Xenopus oocytes : desensitization depending on Ca^<2+> channel α1 subunits." Br.J.Pharmacol.121. 806-812 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Maeda, T.et al.: "Direct evidence for increase in excitatory amino acids release during mossy fiber LTP in hippocampal slices as revealed by the patch sensor methods." Neurosci.Lett.224. 103-106 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kaneko, S.et al.: "Differential regulation of N-and Q-type Ca^<2+> channels by cyclic uncleotides and G-proteins." Life Sci.62. 1543-1547 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakurai, E.et al.: "Involvement of dendritic adhesion molecule telencephalin in hippocampal long-term potentiation." Neuroreport. 9. 881-886 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 中川貴之ら: "クローン化オピオイド受容体発現細胞におけるアゴニスト持続的処置によるアデニル酸シクラーゼ系の過感受性形成メカニズム" 日本薬理学雑誌. 112. 78P-82P (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 南 雅文ら: "蛋白質核酸酵素、第42巻、第3号、335(139)-342(146) 「脳における情報伝達-神経機能素子と素過程」オピオイド受容体" 共立出版株式会社, 8 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 佐藤公道ら: "神経精神薬理、19、190-203 「ニューロトランスミッター・トゥディ」オピオイド類" 星和書店「神経精神薬理」, 14 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ozawa, T.et al.: "Supersensitization of the adenylyl cyclase system in chinese hamster ovary cells co-expressing cloned opioid receptors and G_Z, a PTX-insensitive G-protein." Neurosci.Lett.(in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kaneko, S.et al.: "Inhibition of Ca ^<2+> channel current by mu-and kappa-opipid receptors coexpressed in Xe-nopus oocytes : desensitization depending on Ca^<2+> channel alpha1 subunits." Br.J.Pharmacol.121. 806-812 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Maeda, T.et al.: "Direct evidence for increase in excitatory amino acids release during mossy fiber LTP in hippocampal slices as revealed by the patch sensor methods." Neurosci.Lett.224. 103-106 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kaneko, S.et al.: "Differential regulation of N-and Q-type Ca^<2+> channels by cyclic nucleotides and G-proteins." Life Sci.62. 1543-1547 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakurai, E.et al.: "Involvement of dendritic adhesion mol-ecule telencephalin in hippocampal long-term potentiation." Neuroreport. 9. 881-886 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nakagawa, T.et al.: "A molecular mechanism for supersensi-tization of adenylyl cyclase system in cloned opioid receptor-transfected cells following sustained opioid treatment." Folia Pharmacol.Jpn.70. 78P-82P (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Minami et al.: "Opioid receptors ; Signal Transduction in the Brain : Functional Components and Fundamental Processes in the Nervous System" Protein, Nucleic acid and Enzyme. 42. 355(139)-342(146) (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Satoh, M.et al.: "Opioids ; Neurotransmitter Today" Jpn.J.Neuropsychopharmacol.19. 190-203 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakurai,E.et al.: "Involvement of dendritic adhesion molecule telencephalin in hippocampal long-term potentiation." Neuro Report. 9. 881-886 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sakurai,E.et al.: "Inhibition by [Arg^8]-vasopressin of long term potentiation in guinea pig hippocampal slice." Jpn.J.Pharmcol.77. 103-105 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okano,K.et al.: "Involvement of spinal substance P and excitatory amino acids in inflammatory hyperalgesia in rats." Jpn.J.Pharmcol.76. 15-22 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomita,Y.et al.: "Intracellualar Ca^<2+> store-operated influx of Ca^<2+> through TRP-R,a rat homolog of TRP,expressed in Xenopus oocytes" Neurosci.Lett.248. 195-198 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kaneko,S.et al.: "Differential regulation of N-and Q-type Ca^<2+> channels by cyclic nucleotides and G-proteins." Life Sci.62. 1543-1547 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.,Maeda et al.: "Direct evidence for increase in excitatory amino acids release during mossy fibler LTP in rat hippocampal slices as revealed by the patch sensor methods." Neurosci.Lett.224. 103-106 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] S.,Kaneko et al.: "Inhibition of Ca^<2+> channel current by μ- and κ-opioid receptors coexpressed in Xenopus oocyte : desensitization dependence on Ca^<2+> channel α1 subunits." Br.J.Pharmacol.121. 806-812 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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