Analysis of changes in the systemic immune response connected to brain function by applying new technology for artificial manipulation of specific-neural brain network

• Project/Area Number: 26640015
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurophysiology / General neuroscience
• Research Institution: Hoshi University
• Principal Investigator: Narita Minoru 星薬科大学, 薬学部, 教授 (40318613)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 脳末梢連関 / 視床下部 / オピオイド神経 / 抗腫瘍免疫 / DREADD / 細胞性免疫 / 光遺伝学的手法 / オプトジェネティクス / 中枢神経系 / がん細胞

Outline of Final Research Achievements

In this research, we investigated the changes in the anti-tumor immune response by an activation of the hypothalamic POMC neurons oriented from the arcuate nucleus (ARC), using optogenetics and designer receptors exclusively activated by designer drugs (DREADD) technology, in order to elucidate how the activation of the central nervous system could affect the innate immune system in the development and progression of cancer. As a result, we found that the activation of the hypothalamic POMC neurons in the ARC may suppress the peripheral tumor growth associated with enhancing cell-mediated immunity via activation of the μ-opioid receptor located in paraventricular nucleus of the hypothalamus (PVN).

Research Products

• [Journal Article] Molecular Understanding of the Acquisition of Resistance to Anti-cancer Drugs Associated with the Exacerbation of Cancer (2016)
  • Author(s): 葛巻直子、成田道子、池上大悟、成田 年
  • Journal Title: YAKUGAKU ZASSHI Volume: 136 Issue: 5 Pages: 699-703
  • DOI: 10.1248/yakushi.15-00262-3
  • NAID: 130005148577
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2016-05-01
  • Peer Reviewed / Open Access
• [Journal Article] Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid (2015)
  • Author(s): Juliandi B, Tanemura K, Igarashi K, Tominaga T, Furukawa Y, Otsuka M, Moriyama N, Ikegami D, Abematsu M, Sanosaka T, Tsujimura K, Narita M, Kanno J, Nakashima K
  • Journal Title: Stem Cell Rep Volume: 5 Issue: 6 Pages: 996-1009
  • DOI: 10.1016/j.stemcr.2015.10.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic mechanisms of chronic pain. (2015)
  • Author(s): Descalzi G, Ikegami D, Ushijima T, Nestler EJ, Zachariou V, Narita M.
  • Journal Title: Trends Neurosci. Volume: 38(4) Issue: 4 Pages: 237-246
  • DOI: 10.1016/j.tins.2015.02.001
  • Peer Reviewed / Open Access
• [Journal Article] Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo (2015)
  • Author(s): Masami Suzuki, Fumiko Chiwaki, Yumi Sawada, Maho Ashikawa, Kazuhiko Aoyagi, Takeshi Fujita, Kazuyoshi Yanagihara, Masayuki Komatsu, Minoru Narita, Tsutomu Suzuki, Hiroshi Nagase, Ryoji Kushima, Hiromi Sakamoto, Takeo Fukagawa, Hitoshi Katai, Hitoshi Nakagama, Teruhiko Yoshida, Yasuhito Uezono, Hiroki Sasaki
  • Journal Title: PLOS ONE Volume: 10(4) Issue: 4 Pages: 1-18
  • DOI: 10.1371/journal.pone.0123407
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pain and emotional dysregulation: Cellular memory due to pain (2015)
  • Author(s): Narita M, Watanabe M, Hamada Y, Tamura H, Ikegami D, Kuzumaki N, Igarashi K.
  • Journal Title: Nihon Shinkei Seishin Yakurigaku Zasshi. Volume: 35 Pages: 89-95
  • Peer Reviewed / Open Access
• [Journal Article] Changes in the expression of IL-6-mediated microRNAs in the dorsal root ganglion under neuropathic pain in mice. (2015)
  • Author(s): Hori N, Narita M, Yamashita A, Horiuchi H, Hamada Y, Kondo T, Watanabe M, Igarashi K, Kawata M, Shibasaki M, Yamazaki M, Kuzumaki N, Inada E, Ochiya T, Iseki M, Mori T, Narita M.
  • Journal Title: Synapse Volume: なし Issue: 8 Pages: 21902-21902
  • DOI: 10.1002/syn.21902
  • Peer Reviewed / Open Access
• [Journal Article] κ Opioid systems regulate angiogenesis in development and tumors. (2015)
  • Author(s): Yamamizu K, Hamada Y, Narita M
  • Journal Title: Br J Pharmacol Volume: 172 Issue: 2 Pages: 268-276
  • DOI: 10.1111/bph.12573
  • Peer Reviewed / Open Access
• [Journal Article] Neuropathic pain-like stimuli change the expression of ribosomal proteins in the amygdala: genome-wide search for a “pain-associated anxiety-related factor”. (2015)
  • Author(s): Saisu H, Igarashi K, Narita M, Ikegami D, Kuzumaki N, Wajima K, Nakagawa T, Narita M.
  • Journal Title: Jpn. J. Pharm. Palliat. Care Sci Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Possible involvement of activated locus coeruleus-noradrenergic neurons in pain-related sleep disorders. (2015)
  • Author(s): Koh K, Hamada A, Hamada Y, Yanase M, Sakaki M, Someya K, Narita M, Kuzumaki N, Ikegami D, Sakai H, Iseki M, Inada E, Narita M.
  • Journal Title: Neurosci Lett. Volume: 589 Pages: 200-6
  • DOI: 10.1016/j.neulet.2014.12.002
  • Peer Reviewed / Open Access
• [Journal Article] Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain. (2014)
  • Author(s): Yamashita A, Hamada A, Suhara Y, Kawabe R, Yanase M, Kuzumaki N, Narita M, Matsui R, Okano H, Narita M.
  • Journal Title: Synapse Volume: 68 Issue: 6 Pages: 235-247
  • DOI: 10.1002/syn.21733
  • Peer Reviewed / Open Access
• [Journal Article] Changes in circadian rhythm for mRNA expression of melatonin 1A and 1B receptors in the hypothalamus under a neuropathic pain-like state. (2014)
  • Author(s): Odo M, Koh K, Takada T, Yamashita A, Narita M, Kuzumaki N, Ikegami D, Sakai H, Iseki M, Inada E, Narita M.
  • Journal Title: Synapse Volume: 68 Issue: 4 Pages: 153-158
  • DOI: 10.1002/syn.21728
  • Peer Reviewed / Open Access
• [Journal Article] Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and the decrease in aquaporins in the colon (2014)
  • Author(s): Sakai H, Sagara A, Matsumoto K, Jo A, Hirosaki A, Takase K, Sugiyama R, Sato K, Ikegami D, Horie S, Matoba M, Narita M.
  • Journal Title: Pharmacol. Res. Volume: 87 Pages: 71-79
  • DOI: 10.1016/j.phrs.2014.05.012
  • Peer Reviewed / Open Access
• [Journal Article] harmacological characterization of standard analgesics on oxaliplatin-induced acute cold hypersensitivity in mice. (2014)
  • Author(s): Zhao M, Nakamura S, Miyake T, So K, Shirakawa H, Tokuyama S, Narita M, Nakagawa T, Kaneko S.
  • Journal Title: J Pharmacol Sci. Volume: 124 Pages: 514-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Augmented bronchial smooth muscle contractility induced by aqueous cigarette smoke extract in rats. (2014)
  • Author(s): Sakai H, Watanabe A, Fujita A, Misawa M, Narita M, Chiba Y.
  • Journal Title: J Smooth Muscle Res. Volume: 50 Pages: 39-47
  • NAID: 130004432186
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mechanisms of cisplatin-induced muscle atrophy. (2014)
  • Author(s): Sakai H, Sagara A, Arakawa K, Sugiyama R, Hirosaki A, Takase K, Jo A, Sato K, Chiba Y, Yamazaki M, Matoba M, Narita M
  • Journal Title: Toxicol Appl Pharmacol Volume: 278 Issue: 2 Pages: 190-199
  • DOI: 10.1016/j.taap.2014.05.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Distribution of aquaporin genes and selection of individual reference genes for quantitative real-time RT-PCR analysis in multiple tissues of the mouse. (2014)
  • Author(s): Sakai H, Sato K, Kai Y, Shoji T, Hasegawa S, Nishizaki M, Sagara A, Yamashita A, Narita M.
  • Journal Title: Can J Physiol Pharmacol Volume: 92 Issue: 9 Pages: 789-796
  • DOI: 10.1139/cjpp-2014-0157
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Orally active opioid μ/δ dual agonist MGM-16, a derivative of the indole alkaloid mitragynine, exhibits potent antiallodynic effect on neuropathic pain in mice. (2014)
  • Author(s): Matsumoto K, Narita M, Muramatsu N, Nakayama T, Misawa K, Kitajima M, Tashima K, Devi LA, Suzuki T, Takayama H, Horie S.
  • Journal Title: J Pharmacol Exp Ther. Volume: 348 Issue: 3 Pages: 383-392
  • DOI: 10.1124/jpet.113.208108
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Moesin in the Development of Morphine Analgesic Tolerance through P-glycoprotein at the Blood-Brain Barrier. (2014)
  • Author(s): Kobori T, Fujiwara S, Miyagi K, Harada S, Nakamoto K, Nakagawa T, Takahashi H, Narita M, Tokuyama S.
  • Journal Title: Drug Metab Pharmacokinet Volume: 29 Pages: 482-9
  • NAID: 130004933556
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 緩和医療／疼痛治療における現状とリバーストランスレーショナルリサーチの最前線：除痛によるがん治療への影響を最先端科学により分析する：求められる包括的緩和医療の統合的分子理解 (2016)
  • Author(s): 成田 年、葛巻 直子、成田 道子、濱田 祐輔、近藤 貴茂
  • Organizer: 日本薬学会第136回年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-29
• [Presentation] ヒト疾患特異的iPS細胞技術を用いた精神・神経変性疾患のメカニズム解明 (2016)
  • Author(s): 葛巻 直子、岡野栄之、成田 年
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-11
• [Presentation] Role of hypothalamic POMC neurons in the anti-tumor immune response (2016)
  • Author(s): 濱田 祐輔、田﨑 慶彦、森田 加奈、伊藤 航、志保井美桜 、 藤森 由梨、成田 道子、田村英紀、鈴木 雅美、葛巻 直子、青木一教、山中章弘、成田 年
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-09
• [Presentation] 腫瘍増殖に対する末梢ならびに中枢における μ- オピオイド受容体刺激による相反的作用;中 枢性 μ-オピオイド神経を介した抗腫瘍効果 (2015)
  • Author(s): 森田 加奈、濱田 祐輔、田﨑 慶彦、近藤 貴茂、志保井美桜、伊藤 航、 藤森 由梨、成田 道子、鈴木 雅美、葛巻 直子、成田 年
  • Organizer: 第9回日本緩和医療薬学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2015-10-04
• [Presentation] オピオイド鎮痛薬の分子薬理学的理解の重要性 (2015)
  • Author(s): 成田 年
  • Organizer: 第9回日本緩和医療薬学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2015-10-03
• [Presentation] 難治性疼痛発現機序探索のための“痛みネットワーク”解析に連動した複合型オミクス解析：ケミカルジェネティクスシステムやゲノムワイド解析の応用 (2015)
  • Author(s): 成田 年
  • Organizer: 第88 回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
  • Invited
• [Presentation] エピジェネティクス修飾異常に伴う”痛みの細胞記憶”の形成 (2014)
  • Author(s): 成田 年
  • Organizer: 第9回臨床ストレス応答学会大会
  • Place of Presentation: 岡山
  • Year and Date: 2014-11-01 – 2014-11-02
  • Invited
• [Presentation] Pain-induced epigenetic cell modification and significance of primary pain-control (2014)
  • Author(s): 成田 年
  • Organizer: IASP 15th World Congress on Pain
  • Place of Presentation: Buenos Aires
  • Year and Date: 2014-10-06 – 2014-10-11
  • Invited
• [Presentation] 疼痛分子神経科学領域の次世代型研究の提案 (2014)
  • Author(s): 成田 年
  • Organizer: 第36回日本疼痛学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-06-20 – 2014-06-21
  • Invited
• [Book] 分子病態薬理学I (2014)
  • Author(s): 成田 年
  • Total Pages: 223
  • Publisher: 京都廣川書店
• [Book] がん疼痛緩和ケア (2014)
  • Author(s): 成田 年
  • Total Pages: 18
  • Publisher: じほう