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Ameliorative Potential of Rengyolone Against CCI-induced Neuropathic Pain in Rats
Biomed Sci Letters 2020;26:310-318
Published online December 31, 2020;  https://doi.org/10.15616/BSL.2020.26.4.310
© 2020 The Korean Society For Biomedical Laboratory Sciences.

Gil-Hyun Lee1,* and Kyung-Yae Hyun2,,*

1Department of Clinical Laboratory Science, Dong-Seo University, Busan 47011, Korea
2Department of Clinical Laboratory Science, Dong-Eui University, Busan 47340, Korea
Correspondence to: Kyung-Yae Hyun. Department of Clinical Laboratory Science, Dong-Eui University, Busan 47340, Korea.
Tel: +82-51-890-2683, Fax: +82-0505-182-6877, e-mail: kyhyun@deu.ac.kr
*Professor.
Received September 13, 2020; Revised October 21, 2020; Accepted November 24, 2020.
 Abstract
The sciatic nerve is the largest nerve among the peripheral nerves, and the damage to the sciatic nerve is caused by mechanical and physical pressure. This is an important disease that consumes a lot of time and money in the treatment process. Among them, research on relieving nerve pain caused by damage to the peripheral sciatic nerve has been made efforts to prevent and treat this disease through various methods such as drugs, natural products, electrical stimulation, exercise therapy, and massage. Existing treatments are not very effective in neurological pain, and countermeasures are needed. Forsythia Fructus, used in this study, has been used as a therapeutic agent for infectious diseases and a pain reliever for cancer from the past, and in past studies, it has been known to properly control the inflammatory response. In this study, rengyolone, a physiologically active substance of Forsythiae Fructus, was administered to rats that caused chronic left nerve pain to verify the pain relief effect. As a result of the experiment, it was found that mechanical pain and cold stimulation pain were significantly reduced in the rengyolone-treated group compared to the non-administered group. In addition, it was found that nerve growth factor (NGF) mRNA expression was significantly reduced and Cyclin-dependent kinase 2 (Cdc2) expression was increased in the rengyolone administration group. This increase in NGF expression is thought to be related to rengyolone's anti-inflammatory regulatory mechanism. It is expected that the reduced NGF was directly involved in pain relief.
Keywords : Forsythiae Fructus, Rengyolone, NGF, Cdc2, Animal behavior
꽌 濡

留먯큹떊寃쎄퀎쓽 넀긽씠굹 吏덊솚 떊寃쎌쓽 蹂묐씠굹 泥숈닔 뇤떊寃쏀빑쓽 蹂묐쑝濡 씤빐 諛쒖깮븷 닔 엳뒗뜲, 洹 以 60~70%뒗 留먯큹떊寃 옄泥댁쓽 蹂묐씠硫 쁽 궗쉶뿉꽌뒗 援먰넻궗怨좎 媛숈 쇅긽꽦 넀긽씠 利앷븯怨 엳떎(Milligan et al., 2005). 洹 以 醫뚭낏떊寃쎌 留먯큹떊寃 媛슫뜲 媛옣 겙 떊寃쎌쑝濡, 醫뚭낏떊寃 넀긽 湲곌퀎쟻, 臾쇰━쟻씤 븬諛뺤씠 媛빐졇 諛쒖깮븯寃 릺硫 떊寃쎌쓽 遺꾪룷瑜 뵲씪꽌 룞넻쓣 씪쑝궎怨 떖븯硫 洹쇰젰븯, 洹쇱쐞異뺤씠 諛쒖깮븯寃 릺뒗 寃껋쑝濡 쑀蹂묐쪧怨 蹂묒쓽 씠솚踰붿쐞媛 꼻쑝硫 移섎즺怨쇱젙뿉꽌 떆媛꾧낵 鍮꾩슜씠 留롮씠 냼紐⑤릺뒗 以묒슂븳 吏덈퀝씠떎(Sch채fers and Sommer, 2007). 씠 以 醫뚭낏 留먯큹떊寃 넀긽뿉 쓽븳 떊寃쏀넻利 셿솕뿉 븳 뿰援щ뒗 빟臾, 泥쒖뿰臾, 쟾湲곗옄洹, 슫룞슂踰, 留덉궗吏 벑 떎뼇븳 諛⑸쾿쓣 넻븯뿬 씠 吏덊솚쓣 삁諛⑺븯怨 移섎즺븯뒗 끂젰씠 씠猷⑥뼱吏怨 엳떎(Attal et al., 2006).

넻利앹 援ъ떖꽦 씪李⑥꽟쑀(C-fiber) 쑀닔꽟쑀(A delta-fiber)쓽 솢꽦솕뿉 쓽빐 쑀諛쒕맂떎怨 븣젮졇 엳쑝硫(Staud et al., 2007), C-쑀빐닔슜湲곕뒗 옄洹뱀씠 뾾쑝硫 솢룞븯吏 븡쑝硫, 쑀빐븳 옄洹뱀뿉 옒 諛섏쓳븳떎怨 븯硫(Djouhri et al., 2006), 鍮꾩젙긽쟻쑝濡 솢꽦솕맂 C-fiber媛 떊寃쎈퀝꽦 넻利(neuropathic pain)뿉 湲곗뿬븳떎怨 븣젮졇 엳떎(Ahlgren et al., 1996; Staud et al., 2008). 떊寃쎌씠 븬諛뺤씠굹 젅떒뿉 쓽빐꽌 넀긽릺硫 넀긽맂 異뺤궘쓽 留먮떒뿉꽌뒗 옱깮븯뒗 쁽긽씠 굹굹硫, 씠윭븳 떊寃쎌 삩룄, 臾쇰━쟻, 솕븰쟻 옄洹뱀뿉 븳 誘쇨컧꽦씠 利앷븳떎怨 븣젮졇 엳떎(Hofmann et al., 2003).

넻利앹쓽 湲곗쟾쓣 씠빐븯怨, 슚怨쇱쟻씤 移섎즺빟臾쇱씠굹 移섎즺踰뺤쓣 媛쒕컻븯뒗 룞臾쇳넻利앸え뜽 븘닔쟻씤 슂냼씠떎. 吏궃 닔떗뀈媛 뿰援ъ옄뱾 닔닠쟻씤 諛⑸쾿, 빟臾 닾뿬 諛⑸쾿, 샊 씠臾쇱쓣 궫엯븯뒗 諛⑸쾿 벑 떎뼇븳 諛⑸쾿쓣 씠슜븯뿬 媛 긽솴뿉 留욌뒗 룞臾쇳넻利앸え뜽쓣 꽕怨꾪븯쑝硫(Bennett and Medicine, 1993), 씠 以 떊寃쎌븬諛 諛⑸쾿쓣 씠슜븯뿬 쑀諛쒗븳 留먯큹떊寃쎈퀝꽦 룞넻紐⑤뜽씠 媛쒕컻릺뼱 삤옯룞븞 씠슜릺뼱 솕떎. Bennett쓽 留뚯꽦쟻씤 븬諛뺤넀긽紐⑤뜽(chronic injury model; CCI) 醫뚭낏떊寃(sciatic nerve)쓽 몮젅瑜 뒓뒯븯寃 臾띠뼱 떊寃쎌뿉 넀긽쓣 二쇰ʼn 씠 諛⑸쾿 궗엺뿉寃뚯꽌 諛쒖깮븯뒗 떊寃쎈퀝꽦 룞넻 利앺썑援곗씠 룞臾쇱뿉寃 쑀궗븯寃 諛쒕퀝븯뒗 寃껋쑝濡 븣젮졇 엳떎(Bennett and Xie, 1988).

떊寃쎈퀝꽦 넻利앸え뜽씠 쑀諛쒕맂 룞臾쇱 옄諛쒗넻, 넻媛 怨쇰, 씠吏덊넻 벑쓣 듅吏뺤쑝濡 븯뒗 留뚯꽦 넻利앹쓣 寃れ쑝硫, 湲곌퀎쟻 옄洹밴낵 뿴 옄洹뱀뿉 誘쇨컧룄媛 利앷븳떎怨 븣젮졇 엳떎(Raghavendra et al., 2003). 엫긽뿉꽌뒗 떊寃쎈퀝由ъ꽦 넻利앹쓣 議곗젅븯湲 쐞븯뿬 援먭컧떊寃쎄퀎쓽 泥섏瑜 넻븳 넻利 셿솕, 븘렪怨 빟臾 닾뿬, lidocaine, capsaicin, 빆슦슱젣, 빆寃쎈젴젣 벑쓽 빟臾 닾뿬, 빆궛솕젣瑜 씠슜븳 reactive oxygen species (ROS) 젣嫄, 留먯큹쓽 寃쏀뵾쟻 떊寃쎌옄洹, 留덉留됱쑝濡 궡씤꽦 넻利 뼲젣怨꾩쓽 솢꽦솕 벑 떎뼇븳 諛⑸쾿쓣 씠슜븯怨 엳떎(Ziegler et al., 1995; Low et al., 1997; Ziegler and reviews, 2008). 넻긽 룞臾쇰え뜽뿉꽌 臾쇱쭏 닾뿬 썑 넻媛 怨쇰쇱쓽 媛먯냼 뿬遺뒗 룞臾쇳뻾룞떎뿕쓣 넻븯뿬 룊媛븯怨 엳쑝硫, 궗슜릺뒗 옄洹뱀쑝濡 湲곌퀎쟻 옄洹, 깋 옄洹, 뿴 옄洹, 쟾湲곗옄洹 벑 떎뼇븯떎(Ahlgren et al., 1996; Decosterd and Woolf, 2000). 넀긽맂 떊寃쎌 옱깮쓣 쐞븯뿬 NF-200, Cdc2, NGF, GNDF, Nrg-1, VEGF, IGF-1 벑 떎뼇븳 씤옄뱾 遺꾨퉬븯硫(Lee et al., 2016), 洹 以 neurotrophic factor濡 븣젮吏 nerve growth factor (NGF)뒗 異뺤궘쓣 蹂댄샇븯硫 異뺤궘쓽 꽦옣쓣 珥됱쭊븿怨 룞떆뿉 뒋諛섏꽭룷(schwann cell)쓽 씠二쇰 룄 myelination쓣 珥됱쭊떆耳 넀긽맂 떊寃 옱깮뿉 愿뿬븳떎怨 븣젮졇 엳떎(Hammarberg et al., 1996; Herzberg et al., 1997; Fine et al., 2002). 꽭룷遺꾩뿴 떒怨 以 꽦옣 2떒怨 泥댁꽭룷遺꾩뿴 떒怨꾨줈쓽 쟾씠怨쇱젙뿉꽌 媛옣 빑떖쟻씤 뿭븷쓣 븯뒗 떒諛깆쭏 씤궛솕 슚냼씤 Cyclin-dependent kinase 2 (Cdc2)뒗 cyclin B 怨꾩뿴쓽 議곗젅 떒諛깆쭏 寃고빀뿉 쓽븯뿬 솢꽦솕븯뒗 寃껋쑝濡 븣젮졇 엳떎(Youn et al., 2002). 넀긽맂 醫뚭낏떊寃쎌뿉꽌 Cdc2媛 솢꽦솕릺怨 씠뒗 넀긽 遺쐞쓽 뒋諛섏꽭룷뿉꽌 쑀룄릺뒗 寃껋쑝濡 諛앺議뚯쑝硫 Cdc2媛 뒋諛섏꽭룷쓽 利앹떇 諛 씠二쇰 솢꽦솕븯뿬 異뺤궘 옱깮뿉 룄쓣 二쇰뒗 寃껋쑝濡 蹂닿퀬릺뿀떎(Wu et al., 2016).

뿰援(Forsythiae Fructus)뒗 뿰援(Forsythia suspensa Vahl) 샊 쓽꽦媛쒕굹由(Forsythia viridissima Lindley)씪怨 遺덈━뒗 臾쇳뫖젅굹臾닿낵쓽 떇臾쇱씠떎(Lee and Keum, 1988). 쟾넻쟻쑝濡 빆뿼利앹옉슜, 빐룆옉슜씠 엳떎怨 븣젮졇 엳쑝硫 떎뼇븳 삎깭쓽 媛먯뿼꽦 솚옄뿉寃 移섎즺젣濡 궗슜릺뼱졇 솕떎(Zhuang et al., 2018). 吏궃 닔뀈媛 뿰援щ뱾뿉 쓽븯硫 뿰援먯뿉뒗 빆뿼利, 빆궛솕, 빆諛붿씠윭뒪, 빆븫, 媛꾧린뒫 蹂댄샇, 떊寃쎌꽭룷 蹂댄샇, 洹몃━怨 떖삁愿怨 蹂댄샇옉슜씠 엳쓬씠 諛앺議뚮떎(Nishibe et al., 1982; Bao et al., 2016; Bao et al., 2017; Dong et al., 2017; Zhang et al., 2018). 쟾 뿰援ъ뿉꽌 뿰援먯쓽 援ъ꽦꽦遺꾩씤 rengyolone뒗 媛꾩뿼룞臾쇰え뜽뿉꽌 빆뿼利앺슚怨쇨 엳뿀쑝硫 뿼利앹꽦궗씠넗移댁씤쓽 諛쒗쁽怨 iNOS 깮꽦쓣 븯떆耳곕떎(Lee et al., 2019). 理쒓렐 떦눊蹂묒꽦 떊寃쎈퀝利 肉먮쭔 븘땲씪 留먯큹꽦 떊寃쎈퀝利앹뿉꽌룄 넻利 怨쇰쇳솕瑜 쑀諛쒗븯뒗 ROS쓽 넻젣媛 以묒슂븯떎뒗 뿰援щ뱾씠 엳쑝硫 ROS 議곗젅 넻利앷꼍媛먰슚怨쇨 吏곸젒쟻씤 愿怨꾧 엳떎怨 븳떎(Fidanboylu et al., 2011; Bachewal et al., 2018). 蹂 뿰援ъ뿉꽌뒗 뿰援먮 怨쇨굅뿉꽌遺꽣 떖媛곹븳 븫솚옄뿉寃 넻利 셿솕젣 슜룄濡 궗슜릺뼱 솕떎뒗 湲곕줉 엳吏留 洹몄뿉 븳 뿰援щ뒗 吏꾪뻾맂 諛붽 뾾뒗 諛 씠瑜 洹쒕챸븯怨좎옄 떎뿕쓣 떎뻾븯쑝硫 냼湲곗쓽 꽦怨쇨 엳뼱 蹂 뿰援ъ뿉 븯뿬 蹂닿퀬븯怨좎옄 븳떎(Zhuang et al., 2018).

긽怨 諛⑸쾿

떎뿕룞臾 諛 떆猷

6二쇰졊 닔而 Sprague-Dawley rat (250~300 g) (n=24)瑜 긽쑝濡 븯뿬 22짹3꼦쓣 쑀吏븳 솚寃쎌뿉꽌 諛/궙 二쇨린瑜 留욎텛怨 臾쇨낵 궗猷뚮 異⑸텇엳 怨듦툒븯쑝硫 1二쇱씪 媛 쟻쓳湲곌컙쓣 몢뿀떎. 紐⑤뱺 룞臾쇱떎뿕 International Association for the Study of Pain쓽 吏移⑥쓣 吏궎硫 떆뻾릺뿀떎(Treede, 2018). 뻾룞 룊媛 쟾 넻利앹옄洹뱀뿉 빐 삁誘쇳븳 諛섏쓳쓣 蹂댁씠뒗 媛쒖껜뒗 뿰援ъ뿉꽌 젣쇅븯떎. 蹂 뿰援щ뒗 룞쓽븰援 룞臾쇱떖쓽쐞썝쉶쓽 洹쒖젙뿉 뵲씪 떎뻾븯떎. 蹂 뿰援ъ뿉 궗슜맂 rengyolone AK Scientific, Inc (San Francisco, MO, USA)뿉꽌 援ъ엯븯쑝硫, 珥 RNA 異붿텧젣씤 TRIzol Invitrogen (Carlsbad, USA)뿉꽌 ONE-STEP RT-PCR Premix kit뒗 Intron (Korea)뿉꽌 援ъ엯븯떎.

醫뚭낏 떊寃쎈퀝꽦 넻利앹쓽 쑀諛

Pentobarbital sodium 55 mg/kg쓣 蹂듦컯 궡 二쇱엯븯怨 遺꾨퉬臾 뼲젣瑜 쐞븯뿬 atropine 0.2 mL쓣 洹쇱쑁二쇱궗留덉랬 썑 눜遺 履 꽭쓣 젣嫄고븯怨 踰좏뵖븸쑝濡 냼룆븯떎. 醫뚯륫 눜怨 뵾遺瑜 젅媛쒗븯뿬 빟 2.0 cm 湲몄씠 젙룄濡 醫뚭낏떊寃쎌쓣 끂異쒖떆궎怨 4.0 chromic catgut濡 1 mm 媛꾧꺽쑝濡 4怨녹뿉 留ㅻ벊쓣 誘몃걚윭吏吏 븡쓣 젙룄쓽 꽭湲곕줈 빟븯寃 寃곗같(ligation)븯떎(Youn et al., 2002). 씠 썑 吏삁븯怨 議곗쭅怨 洹쇱쑁쓣 痢듬퀎濡 젙由ы븯뿬 3~0 떎겕濡 遊됲빀븯怨 뵾遺 냼룆쓣 븳 썑 留덉랬뿉꽌 쉶蹂듭떆耳곕떎.

넻利 痢≪젙 諛⑸쾿

떊寃쎈퀝利 넻利앹뿉 븳 뻾룞寃궗뒗 닔닠 2떆媛 쟾, 닔닠 썑 1, 7, 14, 21씪뿉 嫄몄퀜 떎떆븯떎. 옄諛쒖쟻 넻利앹 븘겕由댄뙋 쐞뿉 룞臾쇱쓣 5遺 媛 쟻쓳떆궓 썑 떎쓬 5遺꾧컙 뮮諛쒖쓣 삱由щ뒗 슏닔瑜 痢≪젙븯쑝硫, 쇅遺옄洹뱀뿉 븳 泥좏쉶諛섏쓳(withdrawal response)쓣 蹂닿린 쐞빐 von Frey filament test (11.4 mN bending force)瑜 떎떆븯떎(Bonin et al., 2014). 떎젣 떎뿕뿉꽌뒗 von Frey filament瑜 닔珥 媛꾧꺽쑝濡 뼇痢 諛쒕컮떏뿉 10쉶 옄洹뱁븯뿬 諛쒖쓽 泥좏쉶諛섏쓳쓽 슏닔瑜 뼸뼱 諛깅텇쑉濡 몴떆븯떎.

諛섏쓳룄(response rate) (%)=numbers of foot withdrawal/numbers of the trials (ten)100

삩룄옄洹뱀뿉 븳 넻利앹쓣 寃궗븯湲 쐞븳 諛⑸쾿 acetone spray test瑜 씠슜븯쑝硫, 뼇痢 뮮떎由ъ뿉 5遺 媛꾧꺽쑝濡 5쉶뵫 二쇱궗湲곕 씠슜 acetone쓣 넻媛 쑀諛 遺쐞뿉 媛븯뿬 泥좏쉶諛섏쓳 슏닔瑜 꽱 떎쓬 諛깅텇쑉쓣 援ы븯떎(Vissers and Meert, 2005).

諛섏쓳룄(response rate) (%)=numbers of foot withdrawal/numbers of trials (five)100

빟臾 닾뿬 諛 깦뵆 닔吏

닔닠 6씪 썑遺꽣 rengyolone 100 關g/kg쓣 븯猷 븳 踰 蹂듦컯 궡濡 二쇱궗븯뒗 援(RN援)怨 룞웾 깮由ъ떇뿼닔瑜 二쇱궗븯뒗 援(saline援), 洹몃━怨 醫뚭낏떊寃쎌쓣 끂異쒖떆궓 썑 寃곗같븯吏 븡怨 뵾遺瑜 遊됲빀븳 쐞닔닠援(sham援)쑝濡 굹늻뼱 떎뿕쓣 吏꾪뻾븯떎. 닔닠 썑 21씪 썑 留덉랬븳 룞臾쇱쓣 씗깮븯쑝硫 닔닠 遺쐞쓽 떊寃쎌“吏곸쓣 닔吏묓븯쑝硫 븸솕吏덉냼뿉꽌 湲됱냽 깋룞 썑 70꼦 珥덉삩 깋옣怨좎뿉 蹂닿븯떎.

議곗쭅뿉꽌 NGF Cdc2쓽 痢≪젙

珥 RNA瑜 뼸湲 쐞빐 TRIzol 떆빟 1 mL쓣 梨꾩랬븳 伊먯쓽 떊寃쎌“吏곸뿉 꽔怨 洹좎쭏솕湲(homogenizer)쓣 씠슜빐 옒寃 遺닚 떎쓬 떎삩뿉 5遺 媛 諛⑹튂븳 썑 chloroform 100 關L瑜 泥④븯뿬 빟 10~20珥 媛 샎빀븯怨 뼹쓬뿉꽌 15遺 媛 諛섏쓳떆궓 떎쓬 4꼦, 12,000 rpm뿉꽌 빟 15遺 媛 썝떖 遺꾨━븯떎. 遺꾨━맂 total RNA瑜 젙웾븳 썑, primer, DERC water 洹몃━怨 ONE-STEP RT-PCR Premix kit瑜 꽔怨 Masercycler gradient (Eppendorf, Hamburg, Germany)瑜 씠슜븯뿬 利앺룺븯떎. 媛 PCR 궛臾쇰뱾쓽 뼇쟻 鍮꾧탳瑜 쐞븯뿬 1X TAE buffer濡 1% agarose gel쓣 留뚮뱾怨 well 떦 媛곴컖쓽 primer瑜 꽔怨 DNA gel loading solution쓣 꽎뼱꽌 loading 븳 썑 100 V뿉꽌 쟾湲 쁺룞쓣 떎떆븯떎. DNA 遺꾨━媛 걹궃 썑 gel쓣 ethidium bromide (EtBr, Sigma)濡 뿼깋븳 썑 UV 븯뿉꽌 솗씤븯떎. 蹂 떎뿕뿉 궗슜븳 rat NGF쓽 뿼湲 꽌뿴 sense CCC-CGA-ATC-CTG-TAG-AGA, antisense CAC-GCA-GGC-TGT-ATC-TAT씠뿀쑝硫, Cdc2쓽 뿼湲 꽌뿴 sense GGG-GAT-TCA-GAA-ATT-GAT-CA, antisense TGT-CAG-AAA-GCT-ACA-TCT-TC씠쑝硫, 棺-actin sense ATG-GTG-GGT-ATG-GGT-CAG-AA, antisense TCC-ATA-TCGTCC-CAG-TTG-GT떎.

넻怨

쟾 썑뿉 븳 鍮꾧탳뒗 Wilcoxon signed rank test瑜 씠슜븯뿬 떎瑜 援 궗씠뿉꽌쓽 鍮꾧탳뒗 Mann-Whitney test瑜 궗슜븯떎. 떎以묐퉬援먯씪 寃쎌슦 Kruskal-Wallis test瑜 궗슜븯怨 궗썑遺꾩꽍쑝濡 Bonferroni's method瑜 씠슜븯떎. 遺꾩꽍뿉 궗슜맂 룊洹좉컪 룊洹좉컪 짹 몴以삤李⑤줈 몴떆븯怨, 쑀쓽닔以(P) 0.05쑝濡 꽕젙븯떎.

寃 怨

씪諛섏쟻씤 뻾룞 뼇긽

紐⑤뱺 긽 룞臾쇱 떊寃 넀긽 썑 젙긽쟻씤 泥댁쨷利앷瑜 蹂댁쑝硫, 닔닠 泥섏튂븳 뮮떎由щ뒗 寃쎈룄 eversion 쁽긽쓣 蹂댁떎. 닔닠 吏 썑 떊寃 넀긽 룞臾쇰뱾 湲곌퀎쟻 옄洹밴낵 삩룄옄洹뱀뿉 븯뿬 怨쇰쇱꽦쓣 蹂댁쑝硫 蹂 떎뿕뿉꽌뒗 50% 씠긽쓽 怨쇰쇰컲쓳룄瑜 蹂댁뿬以 22留덈━쓽 룞臾쇰쭔 뿰냽쟻씤 떎뿕긽씠 릺뿀떎.

떊寃쎈퀝利앹꽦 넻利앹쓽 諛쒖깮

紐⑤뱺 룞臾쇱 닔닠 쟾 von Frey filament 샊 븘꽭넠뿉 븯뿬 嫄곗쓽 諛섏쓳쓣 蹂댁씠吏 븡븯쑝굹 닔닠 썑 7씪 썑遺꽣 닔닠 泥섏튂븯吏 븡 삤瑜몄そ 떎由ъ뿉 鍮꾪븯뿬 留먯큹떊寃쎌씠 넀긽맂 쇊履쎌뿉꽌 씠吏덊넻씠 利앷븯쓬쓣 븣 닔 엳뿀떎(Fig. 1). 7씪 썑遺꽣뒗 뼇履 떎由щ컲쓳쓣 鍮꾧탳븯硫 넻怨꾩쟻쑝濡 쑀쓽븳 李⑥씠媛 엳쓬쓣 븣 닔 엳떎(P<0.01).

Fig. 1. Responsiveness of mechanical and thermal stimuli to both feet. Both feet were stimulated to verify the induction of neuralgia. It was found that the sensitivity to pain stimulation was significantly increased in the left foot that caused neuropathy on the 7th day after surgery.

湲곌퀎쟻씤 씠吏덊넻뿉 븳 빟臾 닾뿬 썑 諛섏쓳

11.0 mN bending force뿉꽌 諛섎났릺뒗 湲곌퀎쟻 옄洹뱀뿉 븳 諛쒖쓽 쉶뵾 鍮덈룄瑜 떆媛꾩뿉 뵲씪 몴떆븯떎(Fig. 2). Sham援곗 湲곌퀎쟻씤 옄洹뱀뿉 嫄곗쓽 諛섏쓳씠 뾾뿀쑝硫 RN援곗뿉꽌 von Frey filament뿉 븳 닔닠 썑 7씪 李⑥뿉 룊洹 諛섏쓳룄뒗 62.58%쑝굹 닔닠 썑 21씪 李⑥뿉 룊洹 41.92%濡 넻怨꾩쟻쑝濡 쑀쓽誘명븳 蹂솕瑜 蹂댁떎(P<0.01). 諛섎㈃ 쐞뼇꽦援곗씤 saline援곗뿉꽌뒗 媛숈 떆湲곗뿉 쑀쓽誘명븳 蹂솕媛 뾾뿀떎(P=0.42). Saline援곌낵 RN援곗쓽 諛섏쓳룄쓽 李⑥씠뒗 7씪 李⑤꽣 諛쒖깮븯湲 떆옉(P=0.02)븯쑝硫 21씪寃쎌뿉 洹 李⑥씠 뜑슧 而ㅼ죱떎(P<0.01). 떊寃쏀넻利앹씠 쑀諛쒕맂 떎뿕룞臾쇱뿉꽌 rengyolone뒗 湲곌퀎쟻씤 씠吏덊넻뿉 븯뿬 넻利 뼲젣옉슜쓣 媛吏怨 엳떎怨 궗猷뚮맂떎.

Fig. 2. Behavioral response to mechanical stimuli in neuropathic pain model. A Response to von Frey filament is used as an index of mechanical allodynia. Mean ± SEM. is the response in sham group, in saline group, and in RN group. Significant difference compared with saline operated group (*; P<0.05, **; P<0.01).

삩룄옄洹뱀쑝濡 쑀諛쒕맂 씠吏덊넻뿉 븳 빟臾 닾뿬 썑 諛섏쓳

븘꽭넠씠 利앸컻릺硫댁꽌 諛쒖깮븯뒗 삩 媛먭컖뿉 븳 씠吏덊넻씠 諛쒖깮븳 떎뿕룞臾쇱뿉꽌 빟臾 닾뿬뿉 뵲瑜 諛섏쓳(Fig. 3)쓣 蹂대㈃ Rengyolone 닾뿬 쟾 븘꽭넠뿉 븳 諛섏쓳 닔닠 썑 7씪 李⑥뿉 룊洹 諛섏쓳룄뒗 59.62%쑝굹 닔닠 썑 21씪 李⑥뿉뒗 룊洹 37.51%濡 쑀쓽誘명븳 븯媛뺤쓣 蹂댁떎(P<0.01). 뿭떆 saline援곗뿉꽌뒗 媛숈 떆湲곗뿉 쑀쓽誘명븳 蹂솕媛 뾾뿀떎(P=0.35). Saline援곌낵 RN援곗쓽 諛섏쓳룄쓽 李⑥씠뒗 7씪 李⑤꽣 諛쒖깮븯湲 떆옉(P<0.01)븯쑝硫 21씪寃쎌뿉 洹 李⑥씠 뜑슧 而ㅼ죱떎(P<0.01). 씠윭븳 寃곌낵뒗 떊寃쏀넻利앸룞臾쇰え뜽뿉꽌 Rengyolone 삩룄옄洹뱀쑝濡 쑀諛쒕맂 씠吏덊넻뿉 븳 뼲젣옉슜 媛吏꾨떎뒗 궗떎쓣 븣 닔 엳뿀떎.

Fig. 3. Behavioral response to thermal stimuli in neuropathic pain model. A Response to Acetone evaporative cooling is used as an index of thermal allodynia. Mean ± SEM. is the response in sham group (n=7), in saline group (n=8), and RN group (n=7). Significant difference compared with saline operated group (**; P<0.01).

NGF Cdc2쓽 痢≪젙 寃곌낵

RN援곗뿉꽌 떊寃 넀긽쓣 쑀諛쒗븳 醫뚭낏떊寃쎌쓣 닔吏묓븯怨 떎瑜 援곗뿉꽌 룞씪븳 遺쐞瑜 梨꾩랬븯뿬 mRNA瑜 痢≪젙븯떎(Fig. 4. A, B). Sham援곗쓽 mRNA 諛쒗쁽쓣 湲곗쑝濡 떎瑜 援곗쓽 떒諛깅컻쁽쓣 긽쟻씤 鍮꾩쑉濡 몴쁽븯떎. RN援곗뿉꽌뒗 NGF mRNA 諛쒗쁽 Saline援곗뿉 鍮꾪븯뿬 28.1% 뜑 쟻寃 諛쒗쁽릺뿀쓬쓣 븣 닔 엳뿀쑝硫 넻怨꾩쟻쑝濡 쑀쓽븳 李⑥씠瑜 蹂댁떎(P<0.01). Cdc2 mRNA 諛쒗쁽 Saline援곌낵 鍮꾧탳븯뿬 RN援곗뿉꽌 39.2% 긽듅븯쑝硫 넻怨꾩쟻쑝濡 쑀쓽븳 李⑥씠瑜 蹂댁떎(P<0.01).

Fig. 4. The mRNA expression of NGF and Cdc2 in sciatic nerve. (A) The mRNA expression of NGF (B) The mRNA expression of Cdc2 After an animal sacrifice, samples were collected from the damaged sciatic nerve and analyzed. **significant difference compared with saline operated group (P<0.01).
怨 李

떊寃쎈퀝꽦 넻利 뿰援ъ뿉뒗 뿬윭 룞臾쇰え뜽쓣 씠슜븷 닔 엳쑝硫, 洹 以 媛옣 쓷븯寃 궗슜릺뒗 紐⑤뜽 chronic injury model (chronic constriction injury, CCI) 紐⑤뜽, 醫뚭낏떊寃 寃곗같紐⑤뜽, 洹몃━怨 泥숈닔썑洹 寃곗같紐⑤뜽 벑씠 엳떎(Bennett and Medicine, 1993). 씠 以 CCI 紐⑤뜽 떊寃쎌쓣 뒓뒯엳 삊李⑺븯뿬 떊寃 궡 遺醫낆씠 諛쒖깮븿쑝濡 넻利앹쓣 쑀諛쒗븯뒗 紐⑤뜽씠떎. 떊寃쎌쓣 젅떒븯뒗 룞臾쇰え뜽씤 寃쎌슦 鍮꾩젙긽쟻씤 떊寃 씎遺꾩씠 떊寃쎈퀝꽦 넻利앹쓣 쑀諛쒗븯뒗 벑 떎냼 긽씠븳 寃곌낵瑜 蹂댁씪 닔 엳뼱 蹂 뿰援ъ뿉꽌뒗 CCI 紐⑤뜽쓣 씠슜븯떎.

떊寃쎈퀝利앹꽦 넻利앹 씪諛섏쟻씤 넻利 쟾떖怨쇱젙怨쇰뒗 떎瑜 떊寃 빐遺븰쟻씤 듅吏뺤쓣 媛吏怨 엳湲 븣臾몄뿉 씪諛섏쟻쑝濡 넻利 셿솕젣濡 궗슜릺뒗 鍮꾩뒪뀒濡쒖씠뱶怨 빆뿼利앹젣굹 븘렪怨 빟臾쇱쓣 룷븿븳 씪諛 吏꾪넻젣뿉 옒 諛섏쓳븯吏 븡뒗떎怨 븣젮졇 엳떎(Finnerup et al., 2005; Attal et al., 2006). 씠윴 鍮꾩젙긽쟻씤 넻利앷컧媛곴린꽦 諛섏쓳뱾씤 떊寃쎈퀝利앹꽦 넻利앹씠 諛쒖깮맂 룞臾쇱뿉꽌뒗 넀긽맂 留먯큹떊寃쎄낵 뿰愿맂 泥숈닔뿉꽌 떊寃쎌쟻쓳쟻(neuroplastic) 蹂솕뱾쓣 愿李고븷 닔 엳떎(Baron, 2006). 留먯큹떊寃쎌쓽 넀긽쑝濡 쑀諛쒕맂 떊寃쎌쟻쓳븰쟻 蹂솕濡 떊寃쎌꽭룷쓽 눜뻾꽦 蹂솕 븿猿 떊寃 넀긽 썝쐞遺뿉꽌 떊寃쎌꽟쑀쓽 蹂꽦쓣 쑀諛쒗븯怨 몴쟻옣湲곗쓽 쐞異뺤쓣 쑀諛쒗븯뒗뜲, 듅엳 怨④꺽洹쇱 깉떊寃쎌諛곗꽦 쐞異뺤씠 諛쒖깮븯硫 洹쇱쑁웾怨 洹쇰젰쓽 媛먯냼, 洹쇱꽟쑀 吏곴꼍쓽 媛먯냼媛 쑀諛쒕릺硫, 洹쇱꽟쑀삎쓽 蹂솚, 꽟쑀꽦 諛 吏諛⑷껐빀 議곗쭅웾쓽 利앷 벑씠 쑀諛쒕맂떎(Baron, 2006; Yao and Sessle, 2018). 뵲씪꽌, 醫뚭낏떊寃 넀긽쓽 移섎즺슚怨 遺꾩꽍쓣 쐞빐 빟臾쇱쓣 닾뿬븳 썑 以묒옱湲곌컙 룞븞 뻾룞븰쟻 愿李, 쑁븞쟻 룊媛, 硫댁뿭議곗쭅븰쟻 룊媛瑜 吏꾪뻾븳떎(Decosterd and Woolf, 2000). 씠 以 뻾룞븰쟻 愿李 빆紐⑹쑝濡쒕뒗 룞臾쇱쓽 議깆쟻쓣 씠슜븯뿬 湲곕뒫쟻 쉶蹂듭쓣 愿李고븷 닔 엳뒗 醫뚭낏떊寃 湲곕뒫吏닔씤 SFI, 뿴 옄洹뱀뿉 븳 넻利 뿭移섎 痢≪젙븯湲 쐞븳 plastar test, 湲곌퀎쟻 옄洹뱀뿉 쓽븳 넻利 뿭移섎 痢≪젙븯뒗 touch test, 洹몃━怨 깋 옄洹뱀뿉 븳 넻利 뿭移섎 痢≪젙븯뒗 깋닔議 諛⑸쾿怨 븘꽭넠利앸컻踰 벑씠 엳떎(Kupers et al., 1992). 蹂 뿰援ъ뿉꽌뒗 湲곌퀎쟻 옄洹밴낵 깋 옄洹뱀쓣 씠슜븯뿬 넻利앹뿉 븳 뿭移섎 뙋젙븯뒗 湲곗〈쓽 諛⑸쾿쓣 닔젙븳 Lee (Lee et al., 2000)쓽 諛⑸쾿쓣 씠슜븯떎. 씠 諛⑸쾿쓽 옣젏 鍮덈룄닔媛 諛섏쓳룄(%)濡 寃곌낵瑜 솚궛븯뿬 痢≪젙븯뿬 蹂대떎 젙웾쟻씤 痢≪젙吏닔瑜 궗슜븳떎뒗 젏씠떎. 쑁븞쟻 룊媛 빆紐⑸뱾濡쒕뒗 Muscle wet weight, 異뺤궘쓽 湲몄씠 諛 吏곴꼍 벑씠 룷븿릺뒗뜲 蹂 뿰援ъ뿉꽌뒗 빟臾쇳닾엯湲곌컙怨 쉶蹂듦린媛꾩쓣 怨좊젮븯뿬 蹂 뿰援ъ쓽 寃곌낵뿉뒗 룷븿븯吏 븡븯떎.

Rengyolone쓽 닾엯 룞臾쇱쓽 留먯큹떊寃 넀긽 썑뿉 諛쒖깮맂 湲곌퀎옄洹 샊 깋媛 씠吏덊넻뿉꽌 쑀쓽븳 吏꾪넻슚怨 蹂댁떎. 룞臾쇰え뜽뿉꽌 留먯큹떊寃 넻利 쑀諛쒗솗由쎌쓣 솗씤븯湲 쐞븯뿬 뼇履 諛쒖뿉 옄洹뱀쓣 룞臾쇳뻾룞룊媛뿉꽌 떆뻾븯쑝硫 떊寃쎌넀긽쓣 씪쑝궓 醫뚯륫뿉 鍮꾪븯뿬 슦痢 諛쒖뿉꽌 쁽븯寃 넂 옄洹 뿭移섎 蹂댁엫쓣 븣 닔 엳뿀떎. 듅씠븳 젏 7씪 씠썑 넀긽릺吏 븡뒗 슦痢 諛쒖뿉꽌 湲곌퀎쟻 옄洹 諛 깋 옄洹뱀뿉 븳 誘쇨컧룄媛 넂븘졇 媛뒗 寃쏀뼢쓣 蹂 닔 엳뒗뜲 씠뒗 留먯큹떊寃쎌쓽 넀긽뿉 쓽븳 援먭컧떊寃쎌쓽 솢꽦솕 넀긽맂 留먯큹떊寃쎄낵 뿰寃곕맂 以묒텛떊寃쎌쓽 떊寃쏀븰쟻 蹂솕 愿젴씠 엳떎뒗 怨쇨굅 뿰援 寃곌낵 뿰愿씠 엳떎怨 궗猷뚮맂떎(Treede, 2018; Lee et al., 2019). 蹂 뿰援ъ뿉꽌 湲곌퀎쟻 옄洹뱀뿉 븳 諛섏쓳룄뒗 RN援곌낵 saline援 紐⑤몢 7씪 씠썑뿉 넻利앸컲쓳룄媛 理쒕移섏쑝硫 씠 썑 븯媛뺥븯뒗 寃쏀뼢쓣 蹂댁떎. 7씪, 14씪, 21씪 紐⑤몢 몢 援 궗씠뿉뒗 넻怨꾩쟻쑝濡 쑀쓽븳 李⑥씠瑜 蹂댁쑝硫 씠뒗 빟臾 닾엯씠 留먯큹떊寃쎈퀝利앹뿉 쓽븳 넻利앹쓣 셿솕떆궓떎怨 蹂 닔 엳뒗 寃곌낵씠떎. 븘꽭넠 쑀諛 깋媛 씠吏덊넻뿉꽌룄 湲곌퀎옄洹 넻利앷낵 쑀궗븳 寃쏀뼢씠 굹궗쑝硫, 湲곌퀎옄洹 넻利앷낵 떎瑜 젏 saline援곗뿉꽌 7씪씠 븘땶 21씪뿉 理쒕諛섏쓳룄媛 굹궃 젏씠떎.

떊寃쎌넀긽 BDNF, neurotropim-3, neurotropin-4/5, NGF 벑 뿬윭 떊寃쎌쁺뼇씤옄瑜 諛쒗쁽룄 蹂솕떆궓떎(Fine et al., 2002). 씠뱾 씤옄뱾 떊寃쎌쓽 옱깮怨 깮꽦뿉 뿭븷쓣 븯뒗 寃껋쑝濡 븣젮졇 엳쑝硫 룞떆뿉 넻利앹쓽 쑀諛쒓낵 源딆 愿怨꾧 엳떎(Low et al., 1997; Fine et al., 2002). NGF뒗 醫뚭낏떊寃쎌쓽 젅떒씠굹 븬諛뺤넀긽 떆 p75 neutrophin receptor 뜑遺덉뼱 넀긽 遺쐞쓽 썝쐞遺 遺꾩젅뿉꽌 諛쒗쁽씠 鍮좊Ⅴ寃 利앷븳떎(Low et al., 1997). 怨쇨굅 뿰援 以 넀긽맂 떊寃쎌뿉 anti-NGF瑜 닾뿬븯硫 넀긽 珥덇린뿉뒗 빆넻利앺슚怨쇰 蹂댁씠뒗 諛섎㈃ 넀긽릺吏 븡 떊寃쎌뿉 NGF瑜 닾뿬븯硫 씠吏덊넻씠 굹궃떎(Ramer and Bisby, 1999). 씠 NGF뒗 떊寃쎌쓽 옱깮뿉 엳뒗 以묐븳 뿭븷쓣 븯吏留 떊寃쎈퀝利 넻利 諛쒖깮뿉꽌 NGF媛 뼱뼡 뿭븷쓣 떞떦븯硫 NGF瑜 李⑤떒븯뒗 寃껋씠 삤엳젮 떊寃쎈퀝利 넻利 移섎즺뿉 룄쓣 以 媛뒫꽦씠 엳떎뒗 二쇱옣룄 엳떎(Hefti et al., 2006). 삉븳 NGF쓽 愿젴맂 넻利앸컻쁽 硫댁뿭怨꾨룄 愿뿬븳떎. 넻利앹쓣 吏媛곹븯뒗 留먯큹쓽 쑀빐닔슜湲(nociceptor)뿉뒗 硫댁뿭닔슜湲곌 떎닔 議댁옱븯뒗뜲, IL-1棺, IL-6, TNF慣, bradykinin, prostanoids 벑씠 넻利 諛쒖깮뿉 긽떦븳 뿭븷쓣 닔뻾븳떎怨 븣젮졇 엳떎(Woolf et al., 1997; Sommer and Sch채fers, 2004). 넀긽맂 떊寃쎌 뿼利앸컲쓳쓣 쑀諛쒗븯怨 cytokine쓽 諛쒗쁽씠 利앷릺硫, 쟾뿼利앹꽦궗씠넗移댁씤쓽 利앷뒗 NGF쓽 諛쒗쁽쓣 利앷떆궎硫 NGF뒗 쑀빐닔슜湲곕 誘쇨컧솕븯뿬 넻利앹쓣 諛쒖깮떆궗 닔 엳떎(Sommer and Sch채fers, 2004; Okuse and biology, 2007). 씠윭븳 쟾뿼利앹꽦궗씠넗移댁씤뿉 븯뿬 빐슚怨쇨 엳뒗 臾쇱쭏씠 넻利 셿솕뿉 슚뒫씠 엳떎뒗 떎닔 뿰援 寃곌낵룄 諛쒗몴릺뿀떎(Okamoto et al., 2001; Milligan et al., 2005; Sch채fers and Sommer, 2007). 蹂 뿰援ъ뿉꽌 궗슜맂 rengyolone 怨쇨굅 뿰援 寃곌낵 빆뿼利 諛 쟾뿼利앹꽦궗씠넗移댁씤 諛쒗쁽쓣 궙異붾뒗 슚뒫씠 엳쑝硫 쟾뿼利앹꽦궗씠넗移댁씤 빐젣 媛숈 湲곗쟾쑝濡 넻利 셿솕뿉 룄씠 맆 寃껋씠씪 삁긽릺뿀떎(Kim et al., 2006; Lee et al., 2019). 醫뚭낏떊寃 넀긽 썑 뒋諛섏꽭룷쓽 利앹떇 쑀룄 떒諛깆쭏씤 Cdc2뒗 理쒓렐 뿰援ъ뿉 쓽븯硫 넀긽맂 醫뚭낏떊寃쎌뿉꽌 떆媛 쓽議댁쟻쑝濡 Cdc2媛 솢꽦솕릺怨 씠뒗 넀긽 遺쐞쓽 뒋諛섏꽭룷뿉꽌 쑀룄릺뒗 寃껋쑝濡 떎떆 Cdc2媛 뒋諛섏꽭룷쓽 利앹떇 諛 꽭룷 씠二 솢꽦솕瑜 利앷떆耳 異뺤궘 옱깮뿉 以묒슂븳 뿭븷쓣 븳떎怨 븳떎(Stagg et al., 2011). 蹂 뿰援ъ뿉 쓽븯硫 saline援곌낵 RN援곗뿉꽌 NGF Cdc2 諛쒗쁽쓽 쑀쓽븳 李⑥씠媛 諛쒖깮븯떎. Sham援곗뿉꽌뿉 NGF Cdc2 諛쒗쁽怨 떎瑜 援곕뱾쓽 諛쒗쁽 쑀쓽븳 李⑥씠瑜 蹂댁씠硫 利앸븯쑝硫 씠뒗 떊寃쎌꽭룷쓽 利앹떇怨 옱깮씠 씠猷⑥뼱吏怨 엳떎怨 궗猷뚮맂떎. 븯吏留 NGF Cdc2 諛쒗쁽 꽌濡 떎瑜 寃쏀뼢쓣 蹂댁씤떎. NGF뒗 RN援곗뿉꽌 諛쒗쁽씠 saline援곗뿉꽌 鍮꾪빐 븯릺뿀쑝硫, Cdc2 諛쒗쁽 洹 諛섎濡 긽듅븳 寃곌낵瑜 蹂댁떎. 癒쇱 Cdc2쓽 諛쒗쁽 利앸뒗 떊寃 옱깮쓣 쐞븳 뒋諛섏꽭룷쓽 利앹떇怨 꽭룷 씠二 솢꽦솕濡 씤븯뿬 몢 援 紐⑤몢 利앸븳 寃껋쑝濡 蹂댁씠硫 븳떖룄 븞맂 吏㏃ 湲곌컙뿉 븘吏 떊寃 옱깮씠 吏꾪뻾릺怨 엳떎뒗 利앷굅씪怨 깮媛곷맂떎. 몢 援곗뿉꽌 Cdc2 諛쒗쁽 李⑥씠媛 엳吏留 궗슜臾쇱쭏씠 떊寃 옱깮뿉 뼱뼚븳 諛⑹떇쑝濡 媛꾩꽠븯怨 엳뒗吏뒗 븘吏 쓽臾몄씤 긽깭씠떎. NGF쓽 諛쒗쁽 뼇긽 rengyolone쓽 닾뿬濡 쟾뿼利앹꽦臾쇱쭏뿉 쁺뼢쓣 二쇱뼱 諛쒗쁽씠 吏릺뿀떎怨 삁긽릺硫 씠윴 뿼利앹꽦臾쇱쭏 李⑤떒 怨쇨굅 뿰援ъ뿉꽌 솗씤븷 닔 엳떎. 뿼利앹꽦臾쇱쭏쓽 李⑤떒 쟾뿼利앹꽦궗씠넗移댁씤쓽 긽듅쓣 吏떆궎硫 씠뿉 NGF쓽 諛쒗쁽뿉룄 쁺뼢쓣 二쇨퀬 엳떎怨 궗猷뚮맂떎.

씠踰 뿰援ъ쓽 紐⑹쟻 떊蹂묐퀝꽦 넻利앹쓣 쑀諛쒗븳 룞臾쇰え뜽뿉꽌 넻利앹쓽 醫낅쪟뿉 뵲씪 뿰援먯쓽 깮由ы솢꽦臾쇱쭏 以 븯굹씤 rengyolone쓽 슚怨쇰 뻾룞븰쟻 룊媛 mRNA 遺꾩꽍쓣 넻빐 븣븘蹂닿퀬옄 븯떎. 떎뿕 寃곌낵瑜 젙由ы븯硫 떎쓬怨 媛숇떎. 1) 떊寃쎈퀝꽦 넻利 諛쒖깮 떆 rengyolone 닾뿬뒗 떊寃쏀넻利앹쓣 寃쎄컧떆궓떎. 2) 떊寃쎈퀝꽦 넻利앹쓽 寃쎄컧 떊寃 옱깮뿉꽌 넻利 쑀諛쒓낵 愿젴엳뒗 NGF쓽 諛쒗쁽 吏 愿젴씠 엳떎怨 삁긽맂떎. 쁽옱 뿰援먯뿉 븳 뿬윭 媛吏 뿰援ш 吏꾪뻾릺怨 엳吏留 빆넻利앹뿉 븳 뿰援щ뒗 吏꾪뻾맂 諛붽 뾾쑝硫 씠뿉 븳 湲곗큹 뿰援щ뒗 李⑦썑 뿰援먯 愿젴맂 빆넻利앹젣 媛쒕컻쓽 湲곗큹媛 맆 寃껋씠씪 삁긽맂떎.

ACKNOWLEDGEMENT

None.

CONFLICT OF INTEREST

The researcher claims no conflicts of interest.

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