Elucidation of drug dependence formation / relapse molecular mechanism focusing on neuroinflammation

• Project/Area Number: 17K15758
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Wakayama Medical University
• Principal Investigator: Saika Fumihiro 和歌山県立医科大学, 医学部, 助教 (10644099)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 薬物依存 / 炎症 / ケモカイン / メタンフェタミン / コカイン / 前頭前皮質 / CPP / ドパミン / CPPテスト / 再燃・再発 / 脳内炎症 / ドパミンアゴニスト / 再発 / ミクログリア / CPP試験 / 薬理学 / 行動実験

Outline of Final Research Achievements

Increased expression of several chemokines was observed in prefrontal cortex (PFC) after administration of addictive drugs. These chemokine receptor antagonists attenuated the increase in place preference due to addictive drugs. Next, the effect of dopamine signaling on chemokine expression in PFC was investigated. Increased chemokine expression as well as place preference by addictive drugs was attenuated by dopamine D1 receptor antagonist, but not dopamine D2 receptor antagonist. In addition, D1 receptor agonist showed increased chemokine expression in PFC and increased place preference. These results suggest that increased chemokine expression mediated by dopamine D1 receptor signals plays an important role in psychological dependence.

Academic Significance and Societal Importance of the Research Achievements

近年、薬物乱用の若年化および多発する依存性薬物による重大な事件・事故により依存症の病態生理に基づく新規薬物治療戦略の確立は社会的な緊急課題となっている。薬物依存は中枢神経系における炎症の一つと位置付けられることより、未だに有効な治療薬が開発されていない薬物依存形成期や治療後においても様々な要因により再び乱用時と同様の渇望を生じる再燃・再発期におけるサイトカインやケモカインなどの炎症性メディエーターの関与を明らかにすることで今後の臨床応用へとつなげたい。

Research Products

• [Journal Article] Chemogenetic Regulation of CX3CR1-Expressing Microglia Using Gi-DREADD Exerts Sex-Dependent Anti-Allodynic Effects in Mouse Models of Neuropathic Pain (2020)
  • Author(s): Fumihiro Saika, Shinsuke Matsuzaki, Daichi Kobayashi, Yuya Ideguchi, Tomoe Y Nakamura, Shiroh Kishioka, Norikazu Kiguchi
  • Journal Title: Frontiers in Pharmacology Volume: 11 Pages: 925-925
  • DOI: 10.3389/fphar.2020.00925
  • Peer Reviewed / Open Access
• [Journal Article] Insufficient efferocytosis by M2-like macrophages as a possible mechanism of neuropathic pain induced by nerve injury. (2020)
  • Author(s): Kobayashi D, Kiguchi N, Saika F, Kishioka S, Matsuzaki S.
  • Journal Title: Biochem Biophys Res Commun Volume: Epub Issue: 1 Pages: 216-223
  • DOI: 10.1016/j.bbrc.2020.02.032
  • Peer Reviewed
• [Journal Article] GRP receptor and AMPA receptor cooperatively regulate itch-responsive neurons in the spinal dorsal horn (2020)
  • Author(s): Kiguchi Norikazu、Uta Daisuke、Ding Huiping、Uchida Hitoshi、Saika Fumihiro、Matsuzaki Shinsuke、Fukazawa Yohji、Abe Manabu、Sakimura Kenji、Ko Mei-Chuan、Kishioka Shiroh
  • Journal Title: Neuropharmacology Volume: 170 Pages: 108025-108025
  • DOI: 10.1016/j.neuropharm.2020.108025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inflammatory Macrophages in the Sciatic Nerves Facilitate Neuropathic Pain Associated with Type 2 Diabetes Mellitus. (2019)
  • Author(s): Saika F, Kiguchi N, Matsuzaki S, Kobayashi D, Kishioka S.
  • Journal Title: J Pharmacol Exp Ther. Volume: 368(3) Issue: 3 Pages: 535-544
  • DOI: 10.1124/jpet.118.252668
  • Peer Reviewed
• [Journal Article] CXCL1 is responsible for cocaine-induced reward in mice. (2018)
  • Author(s): Saika F, Matsuzaki S, Kobayashi D, Kiguchi N, Kishioka S.
  • Journal Title: Neuropsychopharmacol Rep Volume: 38(3) Pages: 145-148
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of CCL7 and CCL2 in reward system mediated through dopamine D1 receptor signaling underlies methamphetamine-induced place preference in mice. (2018)
  • Author(s): Saika F, Kiguchi N, Wakida N, Kobayashi D, Fukazawa Y, Matsuzaki S, Kishioka S.
  • Journal Title: Neurosci Lett. Volume: 665 Pages: 33-37
  • Peer Reviewed
• [Journal Article] Inhibition of peripheral macrophages by nicotinic acetylcholine receptor agonists suppresses spinal microglial activation and neuropathic pain in mice with peripheral nerve injury (2018)
  • Author(s): Kiguchi N, Kobayashi D, Saika F, Matsuzaki S, Kishioka S
  • Journal Title: J Neuroinflammation Volume: 15 Issue: 1 Pages: 96-96
  • DOI: 10.1186/s12974-018-1133-5
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacological Regulation of Neuropathic Pain Driven by Inflammatory Macrophages (2017)
  • Author(s): Kiguchi N, Kobayashi D, Saika F, Matsuzaki S, Kishioka S
  • Journal Title: Int J Mol Sci Volume: 18 Issue: 11 Pages: 2296-2296
  • DOI: 10.3390/ijms18112296
  • Peer Reviewed / Open Access
• [Presentation] DREADDシステムを用いたマクロファージ／ミクログリア機能制御が神経障害性疼痛モデルに及ぼす疼痛抑制効果 (2020)
  • Author(s): 雑賀 史浩、木口 倫一、小林 大地、出口 雄也、松﨑 伸介、岸岡 史郎
  • Organizer: 第93回日本薬理学会年会
• [Presentation] DREADDによるマクロファージ／ミクログリアの抑制は雄性マウスの神経障害性疼痛モデルにおいて抗アロディニア効果を示す (2020)
  • Author(s): 出口 雄也、雑賀 史浩、木口 倫一、小林 大地、松﨑 伸介、岸岡 史郎
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 乾癬モデルマウスの痒みを担う脊髄内調節機構 (2019)
  • Author(s): 木口倫一、雑賀 史浩、松﨑 伸介、岸岡 史郎
  • Organizer: 136回日本薬理学会近畿部会
• [Presentation] 神経障害性疼痛モデルマウスにおけるDREADDシステムを用いたマクロファージ／ミクログリア活性操作 (2019)
  • Author(s): 雑賀史浩、木口倫一、小林大地、松﨑伸介
  • Organizer: 疼痛学会
• [Presentation] Curcumin attenuates methamphetamine-induced conditioned place preference via inhibition of CC chemokine ligand 2 expression (2018)
  • Author(s): F. Saika, N. Kiguchi, D. Kobayashi, S. Matsuzaki , S. Kishioka
  • Organizer: 31th ECNP Congress
  • Int'l Joint Research
• [Presentation] Possible involvement of chemokine ligands in addictive drugs-induced conditioned place preference in mice (2018)
  • Author(s): S. Kishioka, F. Saika, N. Kiguchi, D. Kobayashi, S. Matsuzaki
  • Organizer: 31th ECNP Congress
  • Int'l Joint Research
• [Presentation] α4β2ニコチン性アセチルコリン受容体アゴニストはマウスにおける2型糖尿病性神経障害性疼痛を減弱する (2018)
  • Author(s): F. Saika, N. Kiguchi, D. Kobayashi, S. Matsuzaki , S. Kishioka
  • Organizer: 第４０回日本疼痛学会
• [Presentation] 炎症性マクロファージは神経傷害後のミクログリア活性化および機械的アロディニアを調節する (2018)
  • Author(s): 木口倫一、雑賀史浩、小林大地、松崎伸介、岸岡史郎
  • Organizer: 第４０回日本疼痛学会
• [Presentation] Inflammatory macrophages mediate neuropathic pain caused by type 2 diabetes mellitus (2018)
  • Author(s): N. Kiguchi, F. Saika, D. Kobayashi, S. Matsuzaki , S. Kishioka
  • Organizer: 第18回国際薬理学・臨床薬理学会議（WCP2018）
  • Int'l Joint Research
• [Presentation] Inflammatory macrophages in the injured peripheral nerves facilitate spinal microglial activation and neuropathic pain in mice (2018)
  • Author(s): N. Kiguchi, F. Saika, D. Kobayashi, S. Matsuzaki , S. Kishioka
  • Organizer: 17th IASP World Congress of Pain
  • Int'l Joint Research
• [Presentation] 神経障害性疼痛に関与するマクロファージ/ミクログリアの機能解析 (2018)
  • Author(s): 雑賀史浩、木口倫一、小林大地、松崎伸介、岸岡史郎
  • Organizer: 第134回日本薬理学会近畿部会
• [Presentation] Peripheral pro-inflammation cytokines participate in chronic morphine-induced hyperalgesia in mice. (2017)
  • Author(s): S. Kishioka, F. Saika, N. Kiguchi, S. Matsuzaki
  • Organizer: CPDD
  • Int'l Joint Research
• [Presentation] 傷害神経に浸潤するマクロファージは脊髄ミクログリアの活性化を調節する (2017)
  • Author(s): 木口倫一、雑賀史浩、小林大地、松崎伸介、岸岡史郎
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会
• [Presentation] モルヒネ禁断時の血清コルチコステロン上昇におけるα4β2ニコチン性アセチルコリン受容体の関与 (2017)
  • Author(s): 岸岡史郎、山本千鶴子、小林大地、雑賀史浩、木口倫一、松崎伸介
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会
• [Presentation] 食餌性肥満に及ぼす脱酸梅果汁の抑制効果 (2017)
  • Author(s): 木口倫一、雑賀史浩、小林大地、松崎伸介、岸岡史郎
  • Organizer: 第15回果実酒・果実飲料と健康に関する研究
• [Presentation] クルクミンによるメタンフェタミン誘発精神的依存形成の抑制 (2017)
  • Author(s): 雑賀史浩、木口倫一、小林大地、松崎伸介、岸岡史郎
  • Organizer: 第15回果実酒・果実飲料と健康に関する研究
• [Presentation] 神経傷害後の末梢マクロファージによる脊髄ミクログリア調節作用 (2017)
  • Author(s): 木口倫一、小林大地、雑賀史浩、松崎伸介、岸岡史郎
  • Organizer: 第132回日本薬理学会近畿部会
• [Presentation] Regulation of COPI vesicle transport via Scyl1 methylation under ER-stress (2017)
  • Author(s): S. Matsuzaki, G. Amano, Y.Mori, D. kobayashi, H. Takamura, K. Miyoshi, T. Yoshimura, F. Saika, N. Kiguchi, T. Katayama, S. Kishioka
  • Organizer: ASCB2017
  • Int'l Joint Research