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Effects of endocrine disrupter chemicals on a novel G-protein-coupled neurosteroid receptor

Research Project

Project/Area Number 13833005
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research InstitutionNagasaki University

Principal Investigator

YOSHIDA Akira  Nagasaki University Graduate School of Biomedical Sciences Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (70257187)

Co-Investigator(Kenkyū-buntansha) MIZUNO Kiyonobu  Nagasaki University Graduate School of Biomedical Sciences Assistant Professor, 大学院・医歯薬学総合研究科, 助手 (40311865)
UEDA Hiroshi  Nagasaki University Graduate School of Biomedical Sciences Professor, 大学院・医歯薬学総合研究科, 教授 (00145674)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥2,600,000 (Direct Cost: ¥2,600,000)
Keywordspain / neurosteroid / histamine / mast cell / G protein / phospholipase C / pertussis toxin / progesterone
Research Abstract

The intraplantar injection of dehydroepiandrosterone sulfate (DHEAS), a representative neurosteroid, showed hyperalgesia in the Hargreaves' thermal or automatic paw-pressure mechanical nociception test. The Diphenhydramine (DPH), an H_1 histamine (His) receptor antagonist, blocked the hyperalgesia induced by DHEAS as well as the hyperalgesia induced by His or compound 48/80, a mast cell degranulating agent. The DHEAS-induced hyperalgesia was also blocked by progesterone (PROG), another type of neurosteroid and a putative neurosteroid receptor antagonist. Neither DPH nor PROG showed any changes in the thermal threshold. In the algogenics-induced nociceptive flexor responses test in mice, the flexor responses induced by intraplantar injection of DHEAS were blocked by p,p'-DDE, an endocrine disrupting chemical (EDC) as well as by PROG. P,p'-DDE also blocked the DHEAS-induced hyperalgesia in Hargreaves' thermal nociception test. Besides the hyperalgesic actions, DHEAS increased vascular pe … More rmeability as measured with Evans blue plasma extravasation. Consistent with behavioral studies, it was blocked by DPH, PROG and p,p'-DDE. These results suggest that DHEAS has significant hyperalgesic and vasodilatory actions through His release, and these actions were reversible by PROG and an EDC, p,p'-DDE. Moreover, we demonstrated the presence and characterization of a novel neurosteroid receptor underlying such rapid algogenic actions. In the measurements of β-hexosaminidase release from a mast cell line, RBL-2H3, some agonistic neurosteroids, including DHEAS caused rapid degranulation, and it was blocked by PROG. Pharmacological analyses revealed that the stimulation of putative membrane receptor leads to activation of novel G_<q/11> and phospholipase C, which is followed by [Ca^<2+>]_i increase. We further found that many representative EDCs showed antagonistic actions for DHEAS-induced [Ca^<2+>]_i increase, degranulation and nociception. All these results suggest that the G_<q/11>-coupled neurosteroid receptor may regulate the neuroimmunological activity related to sensory stimulation, and EDCs may exert neuronal actions through a disturbance of this mechanism. Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (5 results)

All Other

All Publications (5 results)

  • [Publications] 内田 仁司: "Neurosteroid-induced hyperalgesia through a histamine release is inhibited by progesterone and p,p'-DDE, an endocrine disrupting chemical"Neurochemi.Int.. 42・5. 401-407 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H. Uchida, K. Mizuno, A. Yoshida, H. Ueda: "Neurosteroid-induced hyperalgesia through a histamine release is inhibited by progesterone and p,p'-DDE, an endocrine disrupting chemical"Neurochem. Int.. 42. 401-407 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 内田 仁司: "Neurosteroid-induced hyperalgesia through a histamine release is inhibited by progesterone and p, p'-DDE, an endocrine disrupting chemical"Neurochemi. Int.. 42・5. 401-407 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 植田弘師: "Metabotropic neurosteroid/sigma-receptor involved in stimulation of nociceptor endings of mice"J Pharmacol Exp Ther.. 298. 703-710 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 植田弘師: "Neurosteroids stimulate G protein-coupled sigma receptors in mouse brain synaptic membrane"Neurosci Res. 41. 33-40 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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