Pain mechanism of hip osteoarthritis in rat model

• Project/Area Number: 19K18487
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Chiba University
• Principal Investigator: Hagiwara Shigeo 千葉大学, 医学部附属病院, 助教 (00706723)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 変形性股関節症 / 炎症性疼痛 / 神経障害性疼痛 / 疼痛機序 / ラット股関節モデル

Outline of Research at the Start

本研究の概要ははラット変形性股関節症モデルを用いて変形性股関節症における病態に基づいて疼痛機序を解明し、新規疾患修飾薬の開発を目指すものである。本研究の計画は①Monoiodoacetate(MIA)投与ラット変形性股関節症モデルにおける組織学的・X線学的な変性の解析によるモデルの適正化、②ラット変形性股関節症モデルにおける炎症性サイトカインの推移・股関節支配神経における疼痛評価・行動評価による病態解明、③新規治療薬による病態改善の評価、を行うことである。

Outline of Final Research Achievements

We investigated the analgesic effects of tramadol and the arthritic changes following tramadol administration in the rat hip osteoarthritis (OA) model using mono-iodoacetate (MIA). The right hip joints of male Sprague-Dawley rats in the Sham group were injected with 25 μl of sterile saline and fluorogold (FG) retrograde neurotracer. We assessed hyperalgesia every week after MIA administration. Histopathological changes and immunoreactive neurons for calcitonin gene-related peptide (CGRP) in dorsal root ganglia (DRG) were evaluated after 4 weeks of treatment. MIA injection into the hip joint led to mechanical hyperalgesia, which was significantly reduced by tramadol administration. Furthermore, daily i.p injection of tramadol significantly suppressed CGRP expression in DRG. Interestingly, OA changes significantly progressed in the MIA + Tramadol group compared to the MIA + Vehicle group.

Academic Significance and Societal Importance of the Research Achievements

変形性股関節症は年齢とともに進行する変性疾患であり、高齢化に伴い症例数は増加の一途を辿っている。治療の基本は薬物などによる保存治療であるが、近年強力な鎮痛薬の出現によりかえって関節変形が増悪することが指摘されている。本研究ではMIA投与によるラット変形性股関節症モデルを作成し、その適正化を行うことで慢性疼痛の評価を可能とした。その上でオピオイド性鎮痛薬であるトラマドール投与を行い、OA疼痛抑制効果と徐痛効果に伴うOAの進行を認めた。強力な鎮痛薬を用いることで除痛効果は得られるもののかえって関節変形は進行したことから、その投与については慎重に考慮する必要性があると考えられた。

Research Products

• [Journal Article] Technical and Conceptual Review on the L5-S1 Oblique Lateral Interbody Fusion Surgery (OLIF51) (2021)
  • Author(s): Orita S, Shiga Y, Inage K, Eguchi Y, Maki S, Furuya T, Aoki Y, Inoue M, Hynes RA, Koda M, Takahashi H, Akazawa T, Nakamura J, et al
  • Journal Title: Spine Surgery and Related Research Volume: 5 Issue: 1 Pages: 1-9
  • DOI: 10.22603/ssrr.2020-0086
  • NAID: 130007975810
  • ISSN: 2432-261X
  • Year and Date: 2021-01-27
  • Peer Reviewed
• [Journal Article] Analgesic effects and arthritic changes following tramadol administration in a rat hip osteoarthritis model (2021)
  • Author(s): Kanno Keijiro、Suzuki‐Narita Miyako、Kawarai Yuya、Hagiwara Shigeo、Yoh Satoshi、Nakamura Junichi、Orita Sumihisa、Inage Kazuhide、Suzuki Takane、Ohtori Seiji
  • Journal Title: Journal of Orthopaedic Research Volume: - Issue: 8 Pages: 1770-1777
  • DOI: 10.1002/jor.25208
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An Anatomic Study of the Relationship Between the Iliocapsularis Muscle and Iliofemoral Ligament in Total Hip Arthroplasty (2021)
  • Author(s): Konno Kenta、Hagiwara Shigeo、Nakamura Junichi、Suzuki Takane、Eguchi Yawara、Ohtori Seiji
  • Journal Title: Arthroplasty Today Volume: 12 Pages: 57-61
  • DOI: 10.1016/j.artd.2021.09.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interobserver and Intraobserver Reliabilities of Three-Dimensional Postoperative Evaluation Software in Total Hip Arthroplasty (2021)
  • Author(s): Konno Kenta、Hagiwara Shigeo、Nakamura Junichi、Kawarai Yuya、Orita Sumihisa、Eguchi Yawara、Ohtori Seiji
  • Journal Title: Advances in Orthopedics Volume: 2021 Pages: 1-9
  • DOI: 10.1155/2021/3705789
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Time-Course Changes in Bone Metabolism Markers and Density in Patients with Osteoporosis Treated with Romosozumab: A Multicenter Retrospective Study (2021)
  • Author(s): Inage Kazuhide、Orita Sumihisa、Eguchi Yawara、Shiga Yasuhiro、Koda Masao、Aoki Yasuchika、Kotani Toshiaki、Akazawa Tsutomu、Furuya Takeo、Nakamura Junichi、et al
  • Journal Title: Yonsei Medical Journal Volume: 62 Issue: 9 Pages: 829-829
  • DOI: 10.3349/ymj.2021.62.9.829
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Percutaneously-quantified advanced glycation end-products (AGEs) accumulation associates with low back pain and lower extremity symptoms in middle-aged low back pain patients (2021)
  • Author(s): Umimura T, Orita S, Inage K, Shiga Y, Maki S, Inoue M, Kinoshita H, Norimoto M, Sato T, Sato M, Suzuki M, Enomoto K, Hozumi T, Mizuki N, Takaoka H, Kim G, Nakamura J, et al
  • Journal Title: Journal of Clinical Neuroscience Volume: 84 Pages: 15-22
  • DOI: 10.1016/j.jocn.2020.12.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Concentrated autologous bone marrow aspirate transplantation versus conservative treatment for corticosteroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus (2021)
  • Author(s): Tomaru Yohei、Yoshioka Tomokazu、Nanakamura Junichi、Sugaya Hisashi、Hagiwara Shigeo、Nawata Kento、Ohtori Seiji、Yamazaki Masashi、Mishima Hajime
  • Journal Title: Journal of Rural Medicine Volume: 16 Issue: 1 Pages: 1-7
  • DOI: 10.2185/jrm.2020-033
  • NAID: 130007965980
  • Peer Reviewed
• [Journal Article] Simultaneous MR neurography and apparent T2 mapping of cervical nerve roots before microendoscopic surgery to treat patient with radiculopathy due to cervical disc herniation: Preliminary results (2020)
  • Author(s): Eguchi Y, Enomoto K, Sato T, Watanabe A, Sakai T, Norimoto M, Yoneyama M, Aoki Y, Suzuki M, Yamanaka H, Tamai H, Kobayashi T, Orita S, Suzuki M, Inage K, Shiga Y, Hirosawa N, Inoue M, Koda M, Furuya T, Nakamura J, et al.
  • Journal Title: Journal of Clinical Neuroscience Volume: 74 Pages: 213-219
  • DOI: 10.1016/j.jocn.2019.08.099
  • Peer Reviewed
• [Journal Article] Pilot study of oblique lumbar interbody fusion using mobile percutaneous pedicle screw and validation by a three-dimensional finite element assessment (2020)
  • Author(s): Eguchi Y, Orita S, Yamada H, Suzuki M, Yamanaka H, Tamai H, Inage K, Narita M, Shiga Y, Inoue M, Norimoto M, Umimura T, Sato T, Suzuki M, Enomoto K, Koda M, Furuya T, Maki S, Hirosawa N, Aoki Y, Nakamura J, et al
  • Journal Title: Journal of Clinical Neuroscience Volume: 76 Pages: 74-80
  • DOI: 10.1016/j.jocn.2020.04.043
  • Peer Reviewed
• [Journal Article] Diagnosis of lumbar radiculopathy using simultaneous MR neurography and apparent T2 mapping (2020)
  • Author(s): Sato T, Eguchi Y, Norimoto M, Inoue M, Enomoto K, Watanabe A, Sakai T, Yoneyama M, Aoki Y, Orita S, Narita M, Inage K, Shiga Y, Umimura T, Sato M, Suzuki M, Takaoka H, Mizuki N, Kim G, Hozumi T, Hirosawa N, Furuya T, Maki S, Nakamura J, et al
  • Journal Title: Journal of Clinical Neuroscience Volume: 78 Pages: 339-346
  • DOI: 10.1016/j.jocn.2020.04.072
  • Peer Reviewed
• [Journal Article] Comparison study of bone strength of the proximal femur with and without hip osteoarthritis by computed tomography-based finite element analysis (2020)
  • Author(s): Sugano Masahiko、Hagiwara Shigeo、Nakamura Junichi、Matsuura Yusuke、Suzuki Takane、Wako Yasushi、Miura Michiaki、Kawarai Yuya、Nawata Kento、Yoshino Kensuke、Konno Kenta、Yoh Satoshi、Ohtori Seiji
  • Journal Title: Journal of Biomechanics Volume: 105 Pages: 109810-109810
  • DOI: 10.1016/j.jbiomech.2020.109810
  • Peer Reviewed
• [Journal Article] Impact of spinal alignment and stiffness on impingement after total hip arthroplasty: a radiographic study of pre- and post-operative spinopelvic alignment (2020)
  • Author(s): Hagiwara Shigeo、Orita Sumihisa、Nakamura Junichi、Inage Kazuhide、Kawasaki Yohei、Shiko Yuki、Eguchi Yawara、Ohtori Seiji
  • Journal Title: European Spine Journal Volume: － Issue: 9 Pages: 2443-2449
  • DOI: 10.1007/s00586-020-06589-z
  • Peer Reviewed
• [Journal Article] Natural history of noise and squeaking in cementless ceramic-on-ceramic total hip arthroplasty (2020)
  • Author(s): Inagaki Kenta、Iida Satoshi、Miyamoto Shuichi、Suzuki Chiho、Nakatani Takushi、Shinada Yoshiyuki、Kawarai Yuya、Hagiwara Shigeo、Nakamura Junichi、Orita Sumihisa、Ohtori Seiji
  • Journal Title: Journal of Orthopaedics Volume: 21 Pages: 544-549
  • DOI: 10.1016/j.jor.2020.09.009
  • Peer Reviewed
• [Journal Article] Treatment of protrusion of the acetabular component after total hip arthroplasty in combination with vascular surgery: a report of three cases. (2020)
  • Author(s): He P, , Yoshino K, Hagiwara S, Nakamura J, Ueda H, Kawarai Y, Sugano M, Nawata K, Konno K, Yoh S, Matsumiya G, Ohtori S.
  • Journal Title: Chiba Medical J. Volume: 96E Pages: 59-65
  • NAID: 120006881364
• [Journal Article] Anatomical Implications Regarding Femoral Nerve Palsy During a Direct Anterior Approach to Total Hip Arthroplasty (2020)
  • Author(s): Yoshino Kensuke、Nakamura Junichi、Hagiwara Shigeo、Suzuki Takane、Kawasaki Yohei、Ohtori Seiji
  • Journal Title: The Journal of Bone and Joint Surgery Volume: 102 Issue: 2 Pages: 137-142
  • DOI: 10.2106/jbjs.19.00667
  • Peer Reviewed
• [Journal Article] Anatomical course of the lateral femoral cutaneous nerve with special reference to the direct anterior approach to total hip arthroplasty. (2019)
  • Author(s): Sugano M, Nakamura J, Hagiwara S, Suzuki T, Nakajima T, Orita S, Akazawa T, Eguchi Y, Kawasaki Y, Ohtori S
  • Journal Title: Mod Rheumatol. Volume: 22 Issue: 4 Pages: 1-6
  • DOI: 10.1080/14397595.2019.1637992
  • Peer Reviewed
• [Journal Article] Predictive value of magnetic resonance imaging for multifocal osteonecrosis screening associated with glucocorticoid therapy. (2019)
  • Author(s): Nawata K, Nakamura J, Hagiwara S, Wako Y, Miura M, Kawarai Y, Sugano M, Yoshino K, Inage K, Orita S, Ohtori S.
  • Journal Title: Mod Rheumatol. Volume: 31 Issue: 3 Pages: 1-6
  • DOI: 10.1080/14397595.2019.1623363
  • Peer Reviewed
• [Journal Article] Analgesic Effect of Duloxetine on an Animal Model of Monosodium Iodoacetate‐Induced Hip Osteoarthritis (2019)
  • Author(s): Kawarai Yuya、Orita Sumihisa、Nakamura Junichi、Miyamoto Shuichi、Suzuki Miyako、Inage Kazuhide、Hagiwara Shigeo、Suzuki Takane、Nakajima Takayuki、Akazawa Tsutomu、Ohtori Seiji
  • Journal Title: Journal of Orthopaedic Research Volume: 38 Issue: 2 Pages: 422-430
  • DOI: 10.1002/jor.24480
  • Peer Reviewed
• [Journal Article] Intra- and interobserver reliability and agreement in three-dimensional computed tomography measurements of component positions after total knee arthroplasty (2019)
  • Author(s): Yoshino Kensuke、Hagiwara Shigeo、Nakamura Junichi、Tsukeoka Tadashi、Tsuneizumi Yoshikazu、Ohtori Seiji
  • Journal Title: The Knee Volume: 26 Issue: 5 Pages: 1102-1110
  • DOI: 10.1016/j.knee.2019.07.001
  • Peer Reviewed
• [Presentation] ラット外科的変形性股関節症モデルにおける経時的関節症性変化と疼痛行動学的評価 (2021)
  • Author(s): 葉 佐俊, 中村 順一, 萩原 茂生, 神野 敬士朗, 矢野 斉, 鶴見 要介, 大鳥 精司
  • Organizer: 第65回日本リウマチ学会総会・学術集会
• [Presentation] 変形性股関節症を伴う脊椎関節炎に対する仰臥位前方アプローチによる人工股関節置換術の小経験 (2021)
  • Author(s): 萩原 茂生, 葉 佐俊, 神野 敬士朗, 矢野 斉, 鶴見 要介, 正田 純平, 平沢 累, 中村 順一, 鈴木 昌彦
  • Organizer: 第65回日本リウマチ学会総会・学術集会
• [Presentation] 単純性股関節炎と化膿性股関節炎 (2021)
  • Author(s): 萩原 茂生, 中村 順一, 大鳥 精司
  • Organizer: 第61回関東整形災害外科学会
• [Presentation] 変形性関節症・軟骨 変形性股関節症における股関節周囲筋の評価 3D MRIを用いた検討 (2020)
  • Author(s): 萩原茂生
  • Organizer: 第64回日本リウマチ学会総会
• [Presentation] インフリキシマブ休薬後関節破壊が進行し人工関節置換術を要した2例 (2020)
  • Author(s): 萩原茂生
  • Organizer: 第49回日本リウマチの外科学会
• [Presentation] 脊椎矢状面アライメントと脊椎可動性に基づいたTHAインプラント設置の検討 (2020)
  • Author(s): 萩原茂生
  • Organizer: 第47回日本股関節学会
• [Presentation] Mono-iodoacetateの濃度の変化によるラット股関節の疼痛閾値の変化に関して (2019)
  • Author(s): 葉 佐俊, 瓦井 裕也, 中村 順一, 萩原 茂生, 折田 純久, 稲毛 一秀, 志賀 康浩, 大鳥 精司
  • Organizer: 日本整形外科学会基礎学術集会
• [Presentation] ラット力学的変形壊死股関節症モデルの検討 (2019)
  • Author(s): 葉 佐俊, 中村 順一, 萩原 茂生, 吉野 謙輔, 神野 敬士朗, 紺野 健太,矢野 斉, 大鳥 精司
  • Organizer: 日本股関節学会
• [Presentation] ラット 変形性股関節症モデルにおけるtramadol投与による除痛効果および関節症性変化についての検討 (2019)
  • Author(s): 神野 敬士朗, 葉 佐俊, 中村 順一, 萩原 茂生, 吉野 謙輔, 紺野 健太, 矢野 斉, 大鳥 精司
  • Organizer: 日本股関節学会
• [Presentation] Mono-iodoacetateの濃度の変化によるラット股関節の疼痛閾値の変化に関して (2019)
  • Author(s): 葉 佐俊, 瓦井 裕也, 中村 順一, 萩原 茂生, 志賀 康浩, 稲毛 一秀, 折田 純久, 大鳥 精司
  • Organizer: 日本疼痛学会
• [Presentation] Diffusion tensor imaging of the sciatic and femoral nerves in osteoarthritis of the hip and osteonecrosis of femoral head (2019)
  • Author(s): Shigeo Hagiwara, Wako Yasushi, Junichi Nakamura, Miura Michiaki, Yawara Eguchi, Yuya Kawarai, Masahiko Sugano, Kenoto Nawata, Kensike Yoshino, Kenta Konno, Satoshi Yo
  • Organizer: International Society for Magnetic Resonance in Medicine
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 下肢牽引装置におけるヒップピロー設置台 (2020)
  • Inventor(s): 萩原茂生、中村順一
  • Industrial Property Rights Holder: 国立大学法人千葉大学、株式会社カームラーナ
  • Industrial Property Rights Type: 意匠
  • Filing Date: 2020
  • Acquisition Date: 2021