臨床上外科手術病人通常在術後會有發炎 (inflammation) 及急性術後疼痛 (actue postoperative pain) 等問題，而術後疼痛一直為醫療機構品質改善計畫重點。因此加強術後疼痛的治療，不但能減輕病患術後疼痛感，也能降低術後併發症及死亡率。術後發炎疼痛和環氧酵素-2 (cyclooxygenase-2, COX-2) 誘導表現有關，進而產生前列腺素的釋放，導致周邊疼痛感受器敏感化和提高脊髓神經元興奮現象，
所以本論文主要目的是使用大鼠腳底切割 (plantar incision) 模式，探討術前預防性的給予COX-2抑制劑SC-236是否更能有效減緩術後的痛覺過敏現象，及減緩術後發炎反應。因此我們使用雄性 Sprague-Dawley 大鼠為模型，利用腳底切割模式於術前或術後注射 SC-236，分別在手術後第4小時、第1天、第2天和第3天觀察 COX-2 表現量，使用 von Frey filaments 測量機械性觸感痛 (mechanical allodynia) 之行為，及使用輻射熱源測量溫度痛覺過敏 (thermal hyperalgesia) 之行為，最後使用即時聚合酶連鎖反應、西方墨點法和免疫組織染色分析 COX-2 表現量，比較手術前後給予 SC-236是否能夠更有效抑制術後疼痛與發炎的問題。在結果顯示術前給予SC-236比手術後給予更有效抑制溫度痛覺過度疼痛的現象，但對於機械性的痛覺過敏則沒有抑制的效果。在皮膚組織方面，使用即時聚合酶連鎖反應分析結果發現，術前給予SC-236於術後第1天和第2天mRNA 的表現量有明顯的降低。在西方墨點和免疫組織染色結果也觀察到術前給予SC-236於術後第4小時和第1天蛋白質表現量也有降低的現象。經由以上的實驗結果，我們認為切割手術前給予SC-236確定能有效減緩因手術所造成的溫度痛覺過度疼痛的現象，在皮膚組織中COX-2的mRNA和蛋白質表現量也有明顯的減少，未來能夠更有效處理手術後的急性術後疼痛。

In clinical situations, most of the patients suffer from inflammation and acute postoperative pain after surgery. Postoperative pain has been emphasized as a very crucial issue in improving the quality of medical care in each medical center. Therefore, management of the postoperative pain is an effective approach to reduce the painful unpleasant feeling, complications, and death rate after surgery. Surgical trauma results in the induction of COX-2, leading to the release of prostaglandins, which sensitize peripheral nociceptors and increase the excitability of spinal neurons, producing pain hypersensitivity in the surrounding uninjured tissue.The purpose of this study is to test the preventive effect of COX-2 inhibitor SC-236 for post-operative pain by rat plantar incision model.Then, we explored whether SC-236 is more effective in reducing the hyperalgesia and inflammation response administered before incision than after incision. Furthermore, we used male Sprague-Dawley rats received plantar incision were used in this study, the rats received subcutaneous injection of SC-236 before or after plantar incision. Behavior teste of mechanical allodynia、thermal hyperalgesia and COX-2 expression level was determined at 4 h and 1, 2, and 3 days after surgery. Mechanical allodynia was measured by mechanical withdrawal threshold that was determined by stimulating with von Frey filaments stimulation. Thermal hyperalgesia was measured by thermal withdrawal thermal tested by radioactive thermal assay. Mechanical allodynia、thermal hyperalgesia and COX-2 expression level were measured at various time points by behavior teste、real-time polymerase chain reaction、western blot and immunohistochemistry. The data from pre-incisional injection of SC-236 was compared with that from post-incisional injection of SC-236.The results revealed pre-incisional injection of COX-2 inhibitor significantly inhibited thermal hyperalgesia but not mechanical allodynia then post-incisional injection of COX-2 inhibitor group. Skin of pre-incisional injection of SC-236 show significant decreased mRNA expression of COX-2 at 1 day and 2 day after incision evidenced by real-time polymerase chain reaction. Western blot and immunohistochemistry also show significant decreased protein expression of COX-2 at 4 hours and 1 day after incision. Therefore, pre-incisional administration of SC-236 could prevent the surgical wound induced thermal hyperalgesia and decrease mRNA and protein expression level of cutaneous COX-2 at 4 hours and one day after surgical incision compared to post-incisional administration of SC-236 .

論文審定書 I
誌謝 II
中文摘要 III
英文摘要 IV
目錄 VI
圖目錄 VIII
中英文名詞縮寫對照表 IX
第 一 章 前言 01
第 二 章 文獻回顧 02
1.疼痛 (Pain) 02
2.發炎 (Inflammation) 06
3.術後疼痛 (Postoperative pain) 08
4.環氧酵素-2 (Cyclooxygenase-2) 09
5.術前鎮痛 (Preemptive analgesia) 13
第 三 章 實驗架構 14
第 四 章 研究方法與材料 15
1.實驗動物 15
2.藥物COX-2抑制劑配置 15
3.腳底切割手術 15
4.實驗動物組別 16
5.動物行為測試 16
5.1機械性觸感痛 (Mechanical allodynia) 16
5.2溫度痛覺過敏 (Thermal hyperalgesia) 17
6.mRNA 轉錄反應 17
7.西方墨點法 20
8.免疫螢光染色 22
第 五 章 研究結果 24
1.腳底切割手術之觀察 24
2.腳底切割前後注射COX-2抑制劑之機械性觸感痛 24
3.腳底切割前後注射COX-2抑制劑的溫度痛覺過敏 25
4.腳底切割手術前後給予COX-2抑制劑對 COX-2 mRNA 的表現情
形 26
5.腳底切割手術前後給予COX-2抑制劑對COX-2的蛋白質表現情
形 27
6.腳底切割手術前後給予COX-2抑制劑對皮膚組織COX-2的表現
情形 28
第 六 章 討論與結論 29
第 七 章 參考文獻 33

圖 目 錄
圖一 腳底切割手術流程圖 44
圖二 腳底切割手術後1天發炎觀察 45
圖三 大鼠模式之腳底切割手術及動物行為測試之流程圖 46
圖四 COX-2抑制劑減緩術後疼痛的機械性觸感痛之行為 47
圖五 COX-2抑制劑減緩術後疼痛的溫度痛覺過敏之行為 48
圖六 腳底切割後COX-2 mRNA的表現 49
圖七 以西方墨點法測量正常和腳底切割手術之腳底皮膚COX-2蛋白質表現 50
圖八 以西方墨點法測量腳底切割手術前後給予SC-236之皮膚組織 COX-2蛋
白質表現 51
圖九 以免疫螢光染色分析腳底切割手術後皮膚組織COX-2蛋白質之表現 52

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