神經病變痛是一種難以治癒之症候群，其發生之原因及其複雜，包括酒精、化療、糖尿病、HIV病毒、自體免疫、神經缺損或缺血等。根據統計，有百分之7至8的人口患有神經病變痛。在世界七個主要藥物市場(美國、日本、法國、德國、義大利、西班牙、英國)每年花費之藥物金額高達240億美元，預測2020年將會達到高達360億美元。一般之止痛藥如非類固醇抗發炎藥物，對於神經病變痛之治療效果不佳，然而第一線用藥gabapatin雖然擁有良好之治療效果，但它也同時有許多副作用(如：麻疹、呼吸困難、臉部腫脹、嘴唇腫脹、喉嚨腫脹)。所以我們需要更有效及更少副作用之藥物來治療神經病變痛。我們利用化學資訊學方法研究一個海洋化合物的前驅物，搜尋到化合物WH4可能具有類似的功能。本研究我們使用坐骨神經慢性壓迫 (chronic constriction injury; CCI)大鼠作為神經病變痛之動物模式。結果發現，WH4具有良好之鎮痛效果，其作用機制可能和能量代謝及褪黑激素的受體有關。同時，我們於實驗中發現WH4無明顯之副作用，未來具潛力成為治療神經病變痛之新藥物。

Neuropathic pain is a syndrome which is difficult to cure, and have many complex causes include alcohol, chemotherapy, diabetes, HIV virus, autoimmune, nerve compression or ischemia, etc. In statistic, there are 7-8 percent of people has neuropathic pain. In seven world major pharmaceutical market (America, Japan, France, Germany, Italy, Spain, United Kingdom), the drugs of neuropathic pain were sold 24 billion dollars, and it will be elevated up to 36 billion dollars in 2020. But the common analgesic drug like nonsteroidal anti-inflammatory drugs (NSAIDs) has no effect. The first-line treatment, Gabapatin, has good efficiency, but it also has severe side effect. (e.g., hives; difficult breathing; swelling of your face, lips, tongue, or throat.) In that, we need to develop more drugs which is more effective and less side effect to treat neuropathic pain. In this study, we used chronic constriction injury (CCI) rat as the animal model of neuropathic pain. We use the modified marine compounds (WH4) as agent. In result, WH4 has excellent analgesic effects. Its analgesic effect is even better than that of Gabapatin.The results showed that the mechanism may be related to melatonin MT2 receptor and metabolism, and the change maybe a new way to treat neuropathic pain. We have not found apparent side effect of WH4 in rat still now, it may be a potential compound to develop a new drug in treating neuropathic pain.

國立中山大學研究生學位論文審定書 i
致謝 ii
中文摘要 iii
Abstract iv
目錄 v
圖目錄 vii
表目錄 xi
中英文對照及縮寫表 xii
前言 1
疼痛定義與種類 1
神經病變痛的流行病學 2
神經病變痛之成因與症狀 3
神經病變痛臨床藥物之市場現況 5
神經病變痛形成機制 8
能量代謝與疼痛之關聯性 14
褪黑激素受體(Melatonin receptor)於神經及疼痛中扮演之角色 18
神經病變型疼痛的藥物開發模式 19
海洋藥物目前的發展 23
研究目的 25
材料與方法 26
實驗動物 26
化合物來源 26
化合物受體結合測試 27
椎管製備及椎管插管手術 28
坐骨神經結紮誘發神經病變性疼痛模式 28
疼痛行為評估方法 29
樣本組織收集及冷凍切片 30
組織免疫化學螢光染色 30
實驗動物設計與分組 32
數據分析 34
結果 37
討論 88
WH4與臨床藥物之效果比較 88
CCI大鼠給予WH4預防CCI手術誘發疼痛行為 89
WH4對於正常大鼠之行為反應 90
CCI大鼠給予WH4之脊髓背角細胞及分子層次的影響 90
WH4對於能量代謝之影響 90
WH4對於發炎之影響 92
WH4對於氧化壓力及血管新生之影響 93
WH4對於褪黑激素MT2亞型受體之作用分析 94
抑制褪黑激素MT2亞型受體活化對WH4於神經病變痛鎮痛作用之影響 96
WH4止痛效果與可能之機轉分析 97
參考文獻 101

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