Challenging research aimed at exploration of novel target for drug discovery based on integrated understanding of brain-intestine interactions

• Project/Area Number: 17K19469
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Pharmaceutical Sciences and related fields
• Research Institution: Hokkaido University
• Principal Investigator: Minami Masabumi 北海道大学, 薬学研究院, 教授 (20243040)
• Research Collaborator: IDE Soichiro ; AMANO Taiju ; NOMURA Hiroshi ; HITORA Natsuko ; YAMAMOTO Ryuta ; SUZUKI Hacchi ; TAKAHASHI Daiki ; YAMAUCHI Naoki ; TAKEDA Hiroshi
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 薬学 / 薬理学 / 脳腸連関 / 情動

Outline of Final Research Achievements

The gastric (upper gastrointestinal tract) and colorectal (lower gastrointestinal tract) distention increased noradrenaline release in the bed nucleus of the stria terminalis (BNST). Because we have previously reported that enhanced noradrenaline neurotransmission in the BNST causes anxiety and aversion, gastric and colorectal distention may induce anxiety and aversion via the enhancement of intra-BNST noradrenaline neurotransmission. Furthermore, we showed that intra-BNST administration of beta-adrenoceptor agonist reduced gastric emptying (suppressed upper gastrointestinal motility), while it increased colonic transit (enhanced lower gastrointestinal motility). Anxiety and stress may cause functional gastrointestinal disorders such as stomach upset and diarrhea via enhanced noradrenaline neurotransmission in the BNST.

Academic Significance and Societal Importance of the Research Achievements

消化管刺激により分界条床核内ノルアドレナリン遊離が亢進すること、さらには、分界条床核内ノルアドレナリン神経情報伝達亢進が消化管活動に影響を及ぼすことを示した本研究成果は、脳腸連関における分界条床核の重要性を示すものである。日常的にも経験する「お腹の調子が悪いと不安やうつになる」、あるいは、「心配なことがあるとお腹の調子が悪くなる」という脳と消化管の間の機能連関のメカニズムの一端を明らかにしたものであり、機能性ディスペプシアや過敏性腸症候群などのストレスに起因する機能性消化管障害の病態メカニズム解明や治療薬創製に役立つことが期待される。

Research Products

• [Journal Article] Activation of the neural pathway from the dorsolateral bed nucleus of the stria terminalis to the central amygdala induces anxiety-like behaviors (2018)
  • Author(s): Naoki Yamauchi, Daiki Takahashi, Yae K. Sugimura, Fusao Kato, Taiju Amano, Masabumi Minami
  • Journal Title: European Journal of Neuroscience Volume: 48 Issue: 9 Pages: 3052-3061
  • DOI: 10.1111/ejn.14165
  • Peer Reviewed / Open Access
• [Journal Article] Roles of noradrenergic transmission within the ventral part of the bed nucleus of the stria terminalis in bidirectional brain-intestine interactions (2018)
  • Author(s): Ide Soichiro、Yamamoto Ryuta、Suzuki Hacchi、Takeda Hiroshi、Minami Masabumi
  • Journal Title: Neuropsychopharmacology Reports Volume: 38 Issue: 4 Pages: 182-188
  • DOI: 10.1002/npr2.12032
  • Peer Reviewed / Open Access
• [Journal Article] Bidirectional brain-gut interactions: Involvement of noradrenergic transmission within the ventral part of the bed nucleus of the stria terminalis (2018)
  • Author(s): Ide Soichiro、Yamamoto Ryuta、Takeda Hiroshi、Minami Masabumi
  • Journal Title: Neuropsychopharmacology Reports Volume: 38 Issue: 1 Pages: 37-43
  • DOI: 10.1002/npr2.12004
  • Peer Reviewed / Open Access
• [Remarks] 北海道大学 大学院薬学研究院 医療薬学部門 医療薬学分野 薬理学研究室
  • URL: http://www.pharm.hokudai.ac.jp/yakuri/index.html