Investigation of pain regulation mechanism via novel intracellular transport modulation factor.

• Project/Area Number: 24592798
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Mukogawa Women's University (2014-2015); Hiroshima University (2012-2013)
• Principal Investigator: Kitayama Tomoya 武庫川女子大学, 薬学部, 講師 (60363082)
• Co-Investigator(Kenkyū-buntansha): MORITA Katsuya 広島文化学園大学, 看護学部, 教授 (10116684)
• Co-Investigator(Renkei-kenkyūsha): KANEMATSU Takashi 広島大学, 医歯薬保健学研究院, 教授 (10264053)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 神経障害性疼痛 / クロライドイオン / 抑制性シグナル / 亜鉛 / 疼痛 / PRIP / 亜鉛イオン / KCC2

Outline of Final Research Achievements

To determine the involvement of PRIPs in pain sensation, a hind paw withdrawal test was performed before and after partial sciatic nerve ligation (PSNL) in PRIPs knockout mice (DKO). DKO mice that underwent PSNL surgery showed hard-wired ipsilateral paw withdrawal threshold. To further investigate the inverse phenotype in DKO mice, we produced mice with specific siRNA-mediated knockdown of PRIPs in the spinal cord. Consistent with the phenotypes of KO mice, PRIPs knockdown (DKD) mice with PSNL showed decreased pain-related behavior. This indicates that reduced expression of both PRIPs in the spinal cord induces resistance towards a painful sensation. The expression of KCC2, which controls the balance of neuronal excitation and inhibition, was normal level in DKO mice after PSNL. Suppressed expression of PRIPs induces an elevated expression of KCC2 in the spinal cord, resulting in inhibition of nociception and amelioration of neuropathic pain in DKO mice.

Research Products

• [Journal Article] Palliation of bone cancer pain by antagonists of platelet-activating factor receptors. (2014)
  • Author(s): 3.Morita K., Shiraishi S., Motoyama N., Kitayama T., Kanematsu T., Uezono Y., Dohi T.
  • Journal Title: PLoS One Volume: 9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Relief cancer pain by glycine transporter inhibitors. (2014)
  • Author(s): 1.Motoyama N., Morita K., Shiraishi S., Kitayama T., Kanematsu T., Uezono Y., Dohi T.
  • Journal Title: Anesthesia & analgesia. Volume: 119 Pages: 988-995
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phospholipase C-related but catalytically inactive protein modulates pain behavior in a neuropathic pain model in mice (2013)
  • Author(s): Kitayama et al
  • Journal Title: Molecular Pain Volume: 9 Pages: 23-23
  • DOI: 10.1186/1744-8069-9-23
  • Peer Reviewed
• [Presentation] 細胞内亜鉛濃度変化に伴う神経障害性疼痛発症機序 (2015)
  • Author(s): 北山友也
  • Organizer: 日本薬理学会近畿部会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
  • Year and Date: 2015-11-20
• [Presentation] Down regulation of zinc transporter 1 induces neuropathic pain via BDNF-KCC2 signaling pathway in spinal cord. (2014)
  • Author(s): 北山友也、森田克也、兼松隆
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台
• [Presentation] PRIP遺伝子欠損マウスで認められる神経因性疼痛寛解作用はKCC2高発現に起因する (2013)
  • Author(s): 北山友也 森田克也 Rizia Sultana 兼松隆
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡