Mechanisms of gene regulation intrinsic for human brain in opioid adverse efects

2019 Fiscal Year Research-status Report

• Project/Area Number: 19KK0225
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: 笠井 慎也 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 主席研究員 (20399471)
• Co-Investigator(Kenkyū-buntansha): 池田 和隆 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 分野長 (60281656) ; 村上 浩子 (古田島浩子) 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 研究員 (60619592) ; 田中 美歩 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 研究員 (40788155) ; 田中 宏樹 旭川医科大学, 医学部, 助教 (70596155)
• Project Period (FY): 2019-10-07 – 2025-03-31
• Keywords: オピオイド / 鎮痛薬 / 死後脳 / エピゲノム / 副作用

Outline of Annual Research Achievements

2019年度は、当初の予定通り海外共同研究機関であるKarolinska Institutet, Swedenにて本研究の関係者が集まり（日本側参加者：笠井、田中（宏）助教、スウェーデン側参加者：Druid教授、Alkass博士、Bogdanovic教授）で打ち合わせを行った。Tachykinin receptor 1 (TACR1/NK1R)、Somatostatin (SST)、Choline acetyltransferase (CHAT)の免疫染色より、本研究で注目している脳領域であり、麻薬性鎮痛薬の呼吸抑制に関わると予想される延髄のPre-Botzinger Complex領域（preBotC）を特定できる先行論文が報告されているが、pilot研究により、今回解析を行う検体群では再現できないことを研究代表者らは明らかにしており（VINNOVA Marie-Curie Incomming Project, Project Leader: S Kasai）、preBotC領域の抽出方法について相談した。
現在、解析を行う4群（第1群：慢性使用-過剰使用死、第2群：慢性使用-アクシデント死、第3群：非使用-過剰使用死、第4群：対照）のうち、第1, 3群については既に約20検体が回収・保管されており、さらに追加の検体回収が行われている。第2, 4群についても、検体回収の依頼を行った。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

2019年の当初の予定通り、日本側・海外共同研究先関係者の大半が集まり、今後の予定など打ち合わせや相談を行った。

Strategy for Future Research Activity

海外共同研究機関のDruid教授、Alkass博士、Bogdanovic教授と、preBotC領域の特定法について相談し、アトラスや各種免疫染色などによる目的脳領域の精密抽出法を確立する。海外共同研究機関に既に保管済みの、麻薬性鎮痛薬の使用によるヒト死後脳約20検体を研究代表者の所属先に送付し、確立した方法による脳領域抽出を行う。preBotC領域の近接領域を用いてBioanalyzerによりRINを測定し、各検体におけるRNA品質を解析する。目的脳領域のRNAはmicroarrayを用いた全ゲノム遺伝子発現解析を行う。また、海外共同研究機関において、麻薬性鎮痛薬の使用による死後脳の他の脳領域を回収するための申請手続きを進める。
現在、全世界中におけるコロナウィルスの感染拡大で海外共同研究機関での研究実施が難しい状況である。2020年度末までこの状況が継続する場合、以下の予定で進める。
本研究計画では、麻薬性鎮痛薬が引き起こす呼吸抑制など副作用発現における分子メカニズムを、ヒト死後脳とマウスを用いて解析する計画であり、マウスの実験の大半は研究代表者の所属先において行う予定である。マウスにモルヒネやフェンタニルなど各種麻薬性鎮痛薬を投与した副作用発現モデルを作成する。さらに、来年度以降に行うエピゲノム解析のための各種脳細胞（神経細胞や各種グリア細胞など）別の細胞/細胞核分離手法を確立する。

Causes of Carryover

海外共同研究機関との打ち合わせ費用（笠井分）は打ち合わせのための渡欧日程が2020年2月29日～3月7日であったため、2019年度内処理が間に合わず、2020年度に処理を行う予定である。

Research Products

• [Int'l Joint Research] Karolinska Institutet/Linkoping University(スウェーデン)
  • Country Name: SWEDEN
  • Counterpart Institution: Karolinska Institutet/Linkoping University
• [Journal Article] Low temperature induces von-willebrand factor expression via increased early growth response 1 transcriptional activity in splenic sinusoidal endothelial cells. (2020)
  • Author(s): Horioka K, Tanaka H, Isozaki S, Konishi H, Addo L, Takauji S, Druid H.
  • Journal Title: Biochem Biophys Res Commun Volume: 526 Pages: 239-245
  • DOI: 10.1016/j.bbrc.2020.03.073.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of rapamycin on social interaction deficits and gene expression in mice exposed to valproic acid in utero. (2019)
  • Author(s): Kotajima-Murakami H, Kobayashi T, Kashii H, Sato A, Hagino Y, Tanaka M, Nishito Y, Takamatsu Y, Uchino S, Ikeda K.
  • Journal Title: Mol Brain Volume: 12 Pages: 3
  • DOI: 10.1186/s13041-018-0423-2.
  • Peer Reviewed / Open Access
• [Journal Article] Three-dimensional alteration of neurites in schizophrenia. (2019)
  • Author(s): Mizutani R, Saiga R, Takeuchi A, Uesugi K, Terada Y, Suzuki Y, De Andrade V, De Carlo F, Takekoshi S, Inomoto C, Nakamura N, Kushima I, Iritani S, Ozaki N, Ide S, Ikeda K, Oshima K, Itokawa M, Arai M.
  • Journal Title: Transl Psychiatry Volume: 9 Pages: 85
  • DOI: 10.1038/s41398-019-0427-4.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Japanese TR-Cancer Pain research Group. Resistin is a novel marker for postoperative pain intensity. (2019)
  • Author(s): Hozumi J, Sumitani M, Nishizawa D, Nagashima M, Ikeda K, Abe H, Kato R, Kusakabe Y, Yamada Y.
  • Journal Title: Anesth Analg Volume: 128 Pages: 563-568
  • DOI: 10.1213/ANE.0000000000003363.
  • Peer Reviewed
• [Journal Article] Study of effects of ifenprodil in patients with methamphetamine dependence: Protocol for an exploratory, randomized, double-blind, placebo-controlled trial. (2019)
  • Author(s): Kotajima-Murakami H, Takano A, Ogai Y, Tsukamoto S, Murakami M, Funada D, Tanibuchi Y, Tachimori H, Maruo K, Sasaki T, Matsumoto T, Ikeda K.
  • Journal Title: Neuropsychopharmacol Rep Volume: 39 Pages: 90-99
  • DOI: 10.1002/npr2.12050.
  • Peer Reviewed / Open Access
• [Journal Article] Cognitive impairment that is induced by (R)-ketamine is abolished in NMDA GluN2D receptor subunit knockout mice. (2019)
  • Author(s): Ide S, Ikekubo Y, Mishina M, Hashimoto K, Ikeda K.
  • Journal Title: Int J Neuropsychopharmacol Volume: 22 Pages: 449-452
  • DOI: 10.1093/ijnp/pyz025.
  • Peer Reviewed / Open Access
• [Journal Article] Opioid and nondopamine reward circuitry and state-dependent mechanisms. (2019)
  • Author(s): Fujita M, Ide S, Ikeda K.
  • Journal Title: Ann NY Acad Sci Volume: 1451 Pages: 29-41
  • DOI: 10.1111/nyas.13605.
  • Peer Reviewed / Open Access
• [Presentation] 発がんの分子病理学～なぜがんゲノム検査が必要か？～ (2020)
  • Author(s): 田中宏樹
  • Organizer: 第5回細胞研究会勉強会
  • Invited
• [Presentation] 拡大するアディクション問題へアカデミアはどう取り組む. (2019)
  • Author(s): 池田和隆.
  • Organizer: 2019年度アルコール・薬物依存関連学会合同学術総会
  • Invited
• [Presentation] 様々な依存性物質の感受性に共通して寄与する遺伝子多型. (2019)
  • Author(s): 西澤大輔, 池田和隆.
  • Organizer: 2019年度アルコール・薬物依存関連学会合同学術総会
• [Presentation] mTOR signaling pathway plays a key role in non-syndromic autism spectrum disorder. (2019)
  • Author(s): Kotajima H, Kobayashi T, Sato A, Hagino Y, Tanaka M, Nishito Y, Takamatsu Y, Uchino S, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research / Invited
• [Presentation] The role of NMDA receptor GluN2D subunit in the effects of ketamine and its enantiomers. (2019)
  • Author(s): Ide S, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research / Invited
• [Presentation] Transcriptome signatures of opioid misuse with human postmortem medulla. (2019)
  • Author(s): Kasai S, Bogdanovic N, Alkass K, Druid H.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research / Invited
• [Presentation] Usefulness of intracranial self-stimulation method in drug dependence research. (2019)
  • Author(s): Ide S, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research / Invited
• [Presentation] Hippocampal neuronal excitability in dopamine deficient mice during hyperlocomotor activity caused by novel environment exposure. (2019)
  • Author(s): Fujita M, Ochiai Y, Takeda TC, Hagino Y, Kobayashi K, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] Analysis of the effects of serotonin related drugs on hyperlocomotion in dopamine-deficient mice. (2019)
  • Author(s): Ochiai Y, Fujita M, Hagino Y, Kobayashi K, Okiyama R, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] The role of the cerebellum in fear-conditioned bradycardia. (2019)
  • Author(s): Kotajima H, Narumi S, Sakai K, Hashikawa T, Yuzaki M, Yanagihara D.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] Associations between genetic polymorphisms on chromosome 14q32 and effects of opioid analgesics and chronic pain. (2019)
  • Author(s): Kosaki Y, Nishizawa D, Arita H, Hanaoka K, Yajima C, Iseki M, Kato J, Ogawa S, Hiranuma A, Kasai S, Hasegawa J, Nakayama K, Ebata Y, Koukita Y, Ichinohe T, Hayashida M, Fukuda K, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] Association of a candidate locus for human opioid sensitivity identified in a genome-wide association study in patients undergoing laparoscopic-assisted colectomy with postoperative opioid requirements in patients undergoing painful cosmetic surgery. (2019)
  • Author(s): Inoue R, Nishizawa D, Hasegawa J, Nakayama K, Fukuda K, Sumikura H, Hayashida M, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] Association between a protease-activated receptor 2 gene polymorphism and cold water immersion-induced pain sensitivity. (2019)
  • Author(s): Soeda M, Ohka S, Nishizawa D, Suno M, Fukuda K, Ichinohe T, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] 報酬行動の分子基盤 ～ICSSを用いた報酬メカニズムの解析～. (2019)
  • Author(s): 井手聡一郎, 池田和隆.
  • Organizer: 第49回日本神経精神薬理学会
  • Invited
• [Presentation] rs6738544 SNP of STAT4 and rs2298170 SNP of STAT6 are associated with nicotine dependence. (2019)
  • Author(s): Ohka S, Nishizawa D, Hasegawa J, Sato N, Yamada H, Tanioka F, Sugimura H, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] Genome-wide association studies on chronic pain and effects of drugs for the treatment of pain. (2019)
  • Author(s): Nishizawa D, Arita H, Hanaoka K, Yajima C, Iseki M, Kato J, Ogawa S, Hiranuma A, Kasai S, Hasegawa J, Ebata Y, Nakayama K, Hayashida M, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] Association between the rs11726196 single-nucleotide polymorphism within the transient receptor subfamily C member 3 (TRPC3) gene and chronic pain. (2019)
  • Author(s): Aoki Y, Nishizawa D, Yoshida K, Arita H, Hanaoka K, Yajima C, Iseki M, Kato J, Ogawa S, Hiranuma A, Hasegawa J, Kasai S, Takahashi K, Koukita Y, Ichinohe T, Hayashida M, Fukuda K, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] Behavioral sensitization and relapse in mu-, delta- and kappa-opioid receptor knockout mice. (2019)
  • Author(s): Moriya Y, Hall SF, Kasahara Y, Hagino Y, Kieffer BL, Uhl GR, Sora I, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] Study of ifenprodil effects on patients with methamphetamine dependence: study protocol for an exploratory randomized double-blind placebo-controlled trial. (2019)
  • Author(s): Matsumoto T, Kotajima-Murakami H, Takano A, Ogai Y, Funada D, Tanibuchi Y, Tachimori H, Maruo K, Ikeda K.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research
• [Presentation] Behavioural characterisation of the GluN2DR knock-out mouse model in response to S-ketamine and R-ketamine. (2019)
  • Author(s): Du X, Ikeda K, Sundram S, Hill RA.
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019)
  • Int'l Joint Research