Analysis of genetic mechanism for reduced nociceptive response by genome-wide gene expression assay

• Project/Area Number: 24590741
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pain science
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: KASAI Shinya 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)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 疼痛感受性 / 鎮痛薬感受性 / 全ゲノム遺伝子発現 / モデルマウス

Outline of Final Research Achievements

CXBH mice exhibited slightly higher morphine-induced antinociception compared with C57BL/6J and BALB/cBy mice in the hot-plate test but not tail-flick test. CXBH mice exhibited a marked reduction of nociceptive sensitivity, regardless of the type of nociceptive stimulus, with the exception of tail stimulation. Changes in gene expression that corresponded to reduced nociceptive sensitivity in the brains of CXBH mice were observed in 62 transcripts, including pain- and analgesia-related transcripts, in a whole-genome expression assay. The total mRNA expression of opioid receptors was higher in CXBH mice than in C57BL/6J and BALB/cBy mice. However, the expression levels of MOR-1 mRNA, a major transcript of the μ opioid receptor gene, were not different among the C57BL/6J, BALB/cBy, and CXBH strains. In conclusion, supraspinal nociceptive responses were reduced in the CXBH mouse strain, and the expression levels of transcripts were altered in the brain of this strain.

Research Products

• [Journal Article] Association between the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene and postoperative analgesic requirements. (2015)
  • Author(s): Aoki Y, Nishizawa D, Hasegawa J, Kasai S, Yoshida K, Koukita Y, Ichinohe T, Nagashima M, Katoh R, Satoh Y, Tagami M, Hayashida M, Fukuda K, Ikeda K.
  • Journal Title: J Pharmacol Sci Volume: 127 Issue: 3 Pages: 391-393
  • DOI: 10.1016/j.jphs.2015.02.005
  • Peer Reviewed / Open Access
• [Journal Article] Haplotypes of P2RX7 gene polymorphisms are associated with both cold pain sensitivity and analgesic effect of fentanyl. (2014)
  • Author(s): Ide S, Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Hayashida M, Minami M, Ikeda K.
  • Journal Title: Mol Pain Volume: 10 Pages: 75-75
  • DOI: 10.1186/1744-8069-10-75
  • NAID: 120005549601
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Cholinergic System in Hyperactivity in Dopamine-Deficient Mice (2014)
  • Author(s): Hagino Y., Kasai S, Masayo F, Setogawa S, Yamaura H,Yanagihara D, Hashimoto M, Kobayashi K, Meltzer H, Ikeda K
  • Journal Title: Neuropsychopharmacology Volume: - Issue: 5 Pages: 1-10
  • DOI: 10.1038/npp.2014.295
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Association Between <i>KCNJ6</i> (<i>GIRK2</i>) Gene Polymorphism rs2835859 and Post-operative Analgesia, Pain Sensitivity, and Nicotine Dependence (2014)
  • Author(s): Nishizawa D, Fukuda K, Kasai S, Ogai Y, Hasegawa J, Sato N, Yamada H, Tanioka F, Sugimura H, Hayashida M, Ikeda K.
  • Journal Title: Journal of Pharmacological Sciences Volume: 126 Issue: 3 Pages: 253-263
  • DOI: 10.1254/jphs.14189FP
  • NAID: 130004700283
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed / Open Access
• [Journal Article] Factors that affect intravenous patient-controlled analgesia for postoperative pain following orthognathic surgery for mandibular prognathism. (2014)
  • Author(s): Aoki Y, Yoshida K, Nishizawa D, Kasai S, Ichinohe T, Ikeda K, Fukuda K.
  • Journal Title: PLoS One Volume: 9 Issue: 6 Pages: e98548-e98548
  • DOI: 10.1371/journal.pone.0098548
  • Peer Reviewed / Open Access
• [Journal Article] 喫煙行動と相関するオピオイド受容体関連遺伝子多型の解析 (2014)
  • Author(s): 笠井慎也, 西澤大輔, 長谷川準子, 佐藤直美, 谷岡書彦, 椙村春彦, 池田和隆
  • Journal Title: 日本神経精神薬理学会雑誌 Volume: 34 Pages: 53-54
• [Journal Article] 結節性硬化症モデルマウスの自閉症様行動におけるmTORシグナル系の関与 (2014)
  • Author(s): 佐藤敦志, 笠井慎也, 小林敏之, 高松幸雄, 樋野興夫, 池田和隆, 水口雅
  • Journal Title: 日本神経精神薬理学会雑誌 Volume: 34 Pages: 51-52
• [Journal Article] Genome-wide association study identifies a potent locus associated with human opioid sensitivity. (2014)
  • Author(s): Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Aoki Y, Nishi A, Saita N, Koukita Y, Nagashima M, Katoh R, Satoh Y, Tagami M, Higuchi S, Ujike H, Ozaki N, Inada T, Iwata N, Sora I, Iyo M, Kondo N, Won MJ, Naruse N, Uehara-Aoyama K, Itokawa M, Koga M, Arinami T, Kaneko Y, Hayashida M, Ikeda K.
  • Journal Title: Mol Psychiatry Volume: 19(1) Issue: 1 Pages: 55-62
  • DOI: 10.1038/mp.2012.164
  • Peer Reviewed
• [Journal Article] Association between genetic polymorphisms in Cav2.3 (R-type) Ca2+ channels and fentanyl sensitivity in patients undergoing painful cosmetic surgery (2013)
  • Author(s): Ide S, Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Hayashida M, Minami M, Ikeda K
  • Journal Title: PLoS ONE Volume: 8 Issue: 8 Pages: e70694-e70694
  • DOI: 10.1371/journal.pone.0070694
  • NAID: 120005365905
  • Peer Reviewed
• [Journal Article] Genome-wide association study of sensory disturbances in the inferior alveolar nerve after bilateral sagittal split ramus osteotomy (2013)
  • Author(s): Kobayashi D, Nishizawa D, Takasaki Y, Kasai S, Kakizawa T, Ikeda K, Fukuda K
  • Journal Title: Mol Pain Volume: 9 Pages: 34-34
  • DOI: 10.1186/1744-8069-9-34
  • Peer Reviewed
• [Journal Article] Reduced supraspinal nociceptive responses and distinct gene expression profile in CXBH recombinant inbred mice (2013)
  • Author(s): Kasai S, Ikeda K
  • Journal Title: J Pain Volume: 14 Issue: 6 Pages: 648-661
  • DOI: 10.1016/j.jpain.2013.01.773
  • Peer Reviewed
• [Journal Article] ゲノムワイド関連解析による日本人におけるニコチン依存脆弱性関連座位の同定 (2013)
  • Author(s): 西澤大輔, 笠井慎也, 長谷川準子, 佐藤直美, 谷岡書彦, 椙村春彦, 池田和隆
  • Journal Title: 日本神経精神薬理学雑誌 Volume: 33 Pages: 77-79
  • NAID: 10031169397
• [Journal Article] Association between genetic polymorphisms of the β1-adrenergic receptor and sensitivity to pain and fentanyl in patients undergoing painful cosmetic surgery. (2013)
  • Author(s): Moriyama A, Nishizawa D, Kasai S, Hasegawa J, Fukuda K, Nagashima M, Katoh R, Ikeda K
  • Journal Title: J Pharmacol Sci Volume: 121 Pages: 48-57
  • Peer Reviewed
• [Journal Article] Association between the variable number of tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene and sensitivity to analgesics and pain in patients undergoing painful cosmetic surgery (2013)
  • Author(s): Aoki Y, Nishizawa D, Kasai S, Fukuda K, Ichinohe T, Yamashita S, Ikeda K
  • Journal Title: Neurosci Lett Volume: 542 Pages: 1-4
  • DOI: 10.1016/j.neulet.2013.02.039
  • Peer Reviewed
• [Journal Article] The association between beta-adrenergic receptor gene polymorphisms and personality traits. (2012)
  • Author(s): Numajiri M, Aoki J, Nishizawa D, Kasai S, Ogai Y, Ikeda K, Iwahashi K
  • Journal Title: Nihon Shinkei Seishin Yakurigaku Zasshi Volume: 32 Pages: 227-231
  • Peer Reviewed
• [Journal Article] Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex (2012)
  • Author(s): Sato A, Kasai S, Kobayashi T, Takamatsu Y, Hino O, Ikeda K, Mizuguchi M
  • Journal Title: Nat Commun ncomms2295 Volume: 3 Issue: 1 Pages: 1292-1292
  • DOI: 10.1038/ncomms2295
  • Peer Reviewed
• [Presentation] 疾患モデルとしてのマウスとドーパミン関連遺伝子改変マウスの解析 (2015)
  • Author(s): 笠井慎也, 萩野洋子, 池田和隆
  • Organizer: 第10回日本統合失調症学会
  • Place of Presentation: 都市センターホテル（東京都・千代田区）
  • Year and Date: 2015-03-27 – 2015-03-28
  • Invited
• [Presentation] ドーパミン欠損マウスの多動におけるアセチルコリン神経の関与 (2014)
  • Author(s): 萩野洋子, 笠井慎也, 藤田雅代, 瀬戸川将, 山浦洋, 柳原大, 橋本款, 小林和人, 池田和隆
  • Organizer: 第24回日本臨床精神神経薬理学会・第44回日本神経精神薬理学会合同年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2014-11-21
• [Presentation] ドーパミン欠乏マウスモデルを用いたドーパミン非存在下の運動亢進メカニズムの解析 (2014)
  • Author(s): 藤田雅代, 萩野洋子, 笠井慎也, 橋本款, 小林和人, 池田和隆
  • Organizer: 第24回日本臨床精神神経薬理学会・第44回日本神経精神薬理学会合同年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2014-11-21
• [Presentation] Genome-wide association study of sensory disturbances in the inferior alveolar nerve after bilateral sagittal split ramus osteotomy (2014)
  • Author(s): Nishizawa D, Kobayashi D, Takasaki Y, Kasai S, Aoki Y, Hasegawa J, Kakizawa T, Ikeda K, Fukuda K
  • Organizer: The American Society of Human Genetics 64th Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-10-19
• [Presentation] Involvement of NMDA receptor GluN2D subunit in phencyclidine effects (2014)
  • Author(s): Ikeda K, Hagino Y, Kasai S, Yamamoto H
  • Organizer: 16th International Society of Addiction Medicine Annual Meeting
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-10-03
  • Invited
• [Presentation] ニコチン依存脆弱性に影響を及ぼすオピオイド受容体関連遺伝子 (2014)
  • Author(s): 笠井慎也, 椙村春彦, 池田和隆
  • Organizer: 平成26年度アルコール・薬物依存関連学会合同学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-10-03
  • Invited
• [Presentation] ゲノムワイド関連解析によるオレキシン2 受容体遺伝子多型Val308Ile とニコチン依存との関連の同定 (2014)
  • Author(s): 西澤大輔, 笠井慎也, 佐藤直美, 谷岡書彦, 長島誠, 氏家寛, 橋本亮太, 田中雅嗣, 椙村春彦, 池田和隆
  • Organizer: 平成26年度アルコール・薬物依存関連学会合同学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-10-03
• [Presentation] 鎮痛関連遺伝子多型の情報に基づく術後24時間内フェンタニル投与量の個別化 (2014)
  • Author(s): 吉田香織, 西澤大輔, 高北義彦, 長谷川準子, 笠井慎也, 青木謙典, 一戸達也, 福田謙一, 池田和隆
  • Organizer: 第34回鎮痛薬・オピオイドペプチドシンポジウム
  • Place of Presentation: 公益財団法人東京都医学総合研究所（東京都・世田谷区）
  • Year and Date: 2014-09-06
• [Presentation] 外科的顎矯正手術におけるUGT2B7遺伝子多型とフェンタニル薬剤感受性の関連について (2014)
  • Author(s): 村岡渡, 西澤大輔, 長谷川準子, 笠井慎也, 和嶋浩一, 中川種昭, 福田謙一, 池田和隆
  • Organizer: 第34回鎮痛薬・オピオイドペプチドシンポジウム
  • Place of Presentation: 公益財団法人東京都医学総合研究所（東京都・世田谷区）
  • Year and Date: 2014-09-06
• [Presentation] Dopamine-independent motor control and hyperactivity involving acetylcholine systems (2014)
  • Author(s): Kasai S, Hagino Y, Fujita M, Yanagihara D, Kobayashi K, Ikeda K
  • Organizer: 新学術領域「マイクロ精神病態」班会議
  • Place of Presentation: 宮城蔵王ロイヤルホテル（宮城県・蔵王町）
  • Year and Date: 2014-07-20
• [Presentation] Mouse models of tuberous sclerosis complex show autism-related behavioral deficits severer inTsc2 than Tsc1 haploinsufficiency (2014)
  • Author(s): Sato A, Takamatsu Y, Kasai S, Kobayashi T, Hino O, Ikeda K, Mizuguchi M
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-23
• [Presentation] Reduced supraspinal nociceptive responses and distinct gene expression profile in CXBH recombinant inbred mice (2014)
  • Author(s): Kasai S, Ikeda K
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-23
• [Presentation] Associations of an orexin (hypocretin) receptor 2 gene polymorphism with nicotine dependence found in genome-wide and following association studies (2014)
  • Author(s): Nishizawa D, Kasai S, Hasegawa J, Sato N, Tanioka F, Nagashima M, Ujike H, Hashimoto R, Tanaka M, Sugimura H, Ikeda K
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-23
• [Presentation] Genome-wide association study identifies a potent locus associated with human opioid sensitivity. (2013)
  • Author(s): Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Aoki Y, Nishi A, Saita N, Koukita Y, Nagashima M, Katoh R, Satoh Y, Tagami M, Higuchi S, Ujike H, Ozaki N, Inada T, Iwata N, Sora I, Iyo M, Kondo N, Won MJ, Naruse N, Uehara K, Itokawa M, Koga M, Arinami T, Kaneko Y, Hayashida M, Ikeda K.
  • Organizer: European Human Genetics Conference 2013
  • Place of Presentation: Paris, France
• [Presentation] IV-PCA使用状況から分る手術後鎮痛に影響を与える因子の検討. (2013)
  • Author(s): 青木謙典, 吉田香織, 西澤大輔, 笠井慎也, 林田眞和, 池田和隆, 福田謙一.
  • Organizer: 第33回鎮痛薬・オピオイドペプチドシンポジウム
  • Place of Presentation: 神戸
• [Presentation] 鎮痛薬感受性と関連するオピオイドペプチド遺伝子多型の解析. (2013)
  • Author(s): 笠井慎也, 西澤大輔, 林田眞和, 長島誠, 佐藤泰雄, 田上惠, 加藤良二, 池田和隆.
  • Organizer: 第33回鎮痛薬・オピオイドペプチドシンポジウム
  • Place of Presentation: 神戸
• [Presentation] Association between an opioid receptor-related gene polymorphism and smoking in Japanese. (2013)
  • Author(s): Kasai S, Nishizawa D, Hasegawa J, Sato N, Tanioka F, Sugimura H, Ikeda K.
  • Organizer: 3rd Congress of Asian College of Neuropsychopharmacology
  • Place of Presentation: Beijing, China
• [Presentation] Causal role of unregulated mTOR signaling in autism-related behavioral deficits in mouse models of tuberous sclerosis complex. (2013)
  • Author(s): Sato A, Kasai S, Kobayashi T, Takamatsu Y, Hino O, Ikeda K, Mizuguchi M.
  • Organizer: 3rd Congress of Asian College of Neuropsychopharmacology
  • Place of Presentation: Beijing, China
• [Presentation] NMDA receptor channel subunit GluN2D as a key target of phencyclidine. (2013)
  • Author(s): Ikeda K, Hagino Y, Kasai S, Yamamoto H.
  • Organizer: 3rd Congress of Asian College of Neuropsychopharmacology
  • Place of Presentation: Beijing, China
  • Invited
• [Presentation] Genome-wide association study identifies a potent locus associated with human opioid sensitivity. (2013)
  • Author(s): Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Nagashima M, Satoh Y, Higuchi S, Ujike H, Arinami T, Hayashida M, Ikeda K.
  • Organizer: XXIst World Congress of Psychiatric Genetics
  • Place of Presentation: Boston, USA
• [Presentation] 結節性硬化症モデルマウスTsc1，Tsc2ヘテロ欠失マウスおよびTsc1-Tsc2ダブルヘテロ欠失マウスの自閉症様行動. (2013)
  • Author(s): 佐藤敦志, 高松幸雄, 笠井慎也, 田中美歩, 小林敏之, 樋野興夫, 池田和隆, 水口雅.
  • Organizer: 第23回日本臨床精神神経薬理学会・第43回日本神経精神薬理学会合同年会
  • Place of Presentation: 宜野湾
  • Invited
• [Presentation] Reduced supraspinal nociceptive responses and distinct gene expression profile in CXBH recombinant inbred mice. (2013)
  • Author(s): Kasai S, Ikeda K.
  • Organizer: Asian Pain Symposium 2013
  • Place of Presentation: 岡崎
• [Presentation] Association between P2RX7 gene polymorphisms and fentanyl sensitivity in male patients undergoing painful cosmetic surgery. (2012)
  • Author(s): Ide S, Fukuda K, Nishizawa D, Kasai S, Hasegawa J, Hayashida M, Minami M, Ikeda K
  • Organizer: Purine 2012
  • Place of Presentation: 福岡
• [Presentation] Reduced supraspinal nociceptive responses and distinct gene expression profile in CXBH recombinant inbred mice.
  • Author(s): Kasai S, Ikeda K.
  • Organizer: 新学術領域「マイクロ精神病態」班会議
  • Place of Presentation: 名古屋
• [Presentation] 結節性硬化症モデルマウスの自閉症様行動に対するラパマイシンの治療効果.
  • Author(s): 佐藤敦志, 笠井慎也, 高松幸雄, 小林敏之, 樋野興夫, 池田和隆, 水口雅.
  • Organizer: 第１回日本結節性硬化症学会学術総会
  • Place of Presentation: 東京
• [Presentation] Genome-wide association study identified susceptibility loci associated with nicotine dependence in a Japanese population.
  • Author(s): Nishizawa D, Kasai S, Hasegawa J, Sato N, Tanioka F, Sugimura H, Ikeda K
  • Organizer: CINP 2012, 2012.06.06,
  • Place of Presentation: Stockholm
• [Presentation] Genetic mechanisms underlying sensitivity to pain and analgesics: genetically programmed systems inducing primitive emotion.
  • Author(s): Ikeda K, Nishizawa D, Kasai S
  • Organizer: Neuroscience 2012 Satellite Symposium
  • Place of Presentation: 岡崎
  • Invited
• [Presentation] モルヒネ高感受性マウス系統CXBHにおける侵害受容性反応の異常.
  • Author(s): 笠井慎也, 池田和隆
  • Organizer: 第32回鎮痛薬・オピオイドペプチドシンポジウム
  • Place of Presentation: 東京
• [Presentation] 顎顔面審美手術後における術後鎮痛とドーパミンD4 受容体VNTR多型との関連.
  • Author(s): 青木謙典, 西澤大輔, 笠井慎也, 長谷川準子, 林田眞和, 吉田香織, 齋田菜緒子, 髙北義彦, 福田謙一, 池田和隆
  • Organizer: 第22回日本臨床精神神経薬理学会・第42回日本神経精神薬理学会合同年会
  • Place of Presentation: 宇都宮
• [Presentation] 結節性硬化症モデルマウスの自閉症様行動およびラパマイシンによる改善効果.
  • Author(s): 佐藤敦志, 笠井慎也, 高松幸雄, 小林敏之, 樋野興夫, 池田和隆, 水口雅
  • Organizer: 第22回日本臨床精神神経薬理学会・第42回日本神経精神薬理学会合同年会
  • Place of Presentation: 宇都宮
• [Presentation] Genome-wide association study identified susceptibility loci associated with nicotine dependence in a Japanese population.
  • Author(s): Nishizawa D, Kasai S, Hasegawa J, Sato N, Tanioka F, Sugimura H, Ikeda K
  • Organizer: ASHG2012 第62回米国人類遺伝学会
  • Place of Presentation: San Francisco