Does free fatty acid receptor 1 FFAR1 contribute to the development of chronic pain-associated depression ?

• Project/Area Number: 19K09512
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Kagoshima University
• Principal Investigator: OYOSHI Tatsuki 鹿児島大学, 医歯学総合研究科, 客員研究員 (80315407)
• Co-Investigator(Kenkyū-buntansha): 栗原 崇 鹿児島大学, 医歯学域医学系, 准教授 (60282745)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: FFAR1 / GPR40 / 慢性疼痛 / うつ様行動不安様行動 / 三環系抗うつ薬 / コカイン / セロトニン / 移所運動活性 / In vivo マイクロダイアリシス法 / 線条体 / 依存 / うつ病 / in vivoマイクロダイアリシス法 / 疼痛 / in vivoマイクロダイアリシス

Outline of Research at the Start

本研究では① 野生型および欠損マウスに遷延性炎症性疼痛あるいは末梢神経障害性疼痛を誘発させ、経時的にうつ状態を評価し、さらに抗うつ薬の効果を検討する、② ①の過程で、経時的に黒質、線条体、扁桃体、前頭前野等の組織を採取し、遺伝子・タンパク質(モノアミン類のトランスポーター・受容体など) 発現解析、遊離脂肪酸測定を行う、③ ②で解析を行う領野からin vivoマイクロダイアリシスを行い、各種モノアミン遊離量を測定し、FFAR1作動薬・拮抗薬投与の効果を検討する、ことを提案する。本検討から、未だ不明点の多いFFAR1の中枢神経機能が新たに明らかになるとともに、新規抗うつ薬開発への応用が期待される。

Outline of Final Research Achievements

Previous our studies have demonstrated that the free fatty acid receptor 1 (FFAR1) is found to be expressed on descending monoamine neurons and central application of a FFAR1 agonist evokes an endogenous antinociception. Furthermore, we have recently found that FFAR1 signaling also contributes to emotional-related behaviors. Thus, in this study, we have investigated a possible involvement of FFAR1 in the development of pain-associated depression-like behavior in mice.
We observed that complete Freund’s adjuvant (CFA)- and spinal nerve ligation (SNL)-induced mechanical allodynia and depression-like behaviors were more pronounced in FFAR1-/- mice than +/+ mice. Furthermore, we found that tricyclic antidepressants blocked the CFA-, but not SNL-induced depression-like behavior. Our data support that FFAR1 signaling contributes to the development of depression-like behavior in pain condition, and potentiating FFAR1 system may be a new strategy to manage comorbid pain and depression.

Academic Significance and Societal Importance of the Research Achievements

慢性痛患者における精神疾患の併病率は、痛みのない一般人と比較して有意に高いことが、様々な疫学調査から示唆されている。しかし、なぜ慢性疼痛が精神状態に負の影響を与えるのか、その詳しいメカニズムは未だ不明である。
そこで我々の研究グループは、疼痛と情動行動に影響を与える分子としてFFAR1に着目し、FFAR1遺伝子欠損マウスでは疼痛症状とうつ様行動が悪化すること、疼痛症状が強く、慢性化しやすい末梢神経障害性疼痛モデルマウスでは、三環系抗うつ薬の薬効が消失していたことなどから、FFAR1は疼痛慢性化と負情動行動発症調節に重要な分子であることが示唆された。

Research Products

• [Journal Article] FFAR1/GPR40 Contributes to the Regulation of Striatal Monoamine Releases and Facilitation of Cocaine-Induced Locomotor Activity in Mice (2021)
  • Author(s): Yuko Sadamura, Shanta Thapa, Ryota Mizunuma, Yuki Kambe, Akira Hirasawa, Kazuo Nakamoto, Shogo Tokuyama, Koji Yoshimoto, Kazunori Arita, Atsuro Miyata, Tatsuki Oyoshi and Takashi Kurihara
  • Journal Title: Frontiers in Pharmacology Volume: 12 Pages: 699026-699026
  • DOI: 10.3389/fphar.2021.699026
  • Peer Reviewed / Open Access
• [Presentation] Involvement of free fatty acid receptor 1 (FFAR1) in the regulation of striatal monoamine releases and cocaine-induced locomotor activity in mice. (2019)
  • Author(s): Shanta Thapa, Yuko Sadamura, Ryota Mizunuma, Yuki Kambe, Akira Hirasawa, Kazuo Nakamoto, Shogo Tokuyama, Kazunori Arita, Koji Yoshimoto, Atsuro Miyata, Tatsuki Oyoshi, and Takashi Kurihara
  • Organizer: 6 the congress of AsCNP
  • Int'l Joint Research
• [Presentation] Possible involvement of free fatty acid receptor 1 (FFAR1) in the regulation of striatal serotonin release and cocaine-induced locomotor activity in mice. (2019)
  • Author(s): Shanta Thapa, Yuko Sadamura, Ryota Mizunuma, Yuki Kambe, Akira Hirasawa, Kazuo Nakamoto, Shogo Tokuyama, Kazunori Arita, Koji Yoshimoto, Atsuro Miyata, Tatsuki Oyoshi, and Takashi Kurihara
  • Organizer: 第11回トランスポーター研究会九州部会