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研究生:薛聖芬
論文名稱:脊管內施予藥物治療對疼痛控制之研究
論文名稱(外文):Intrathecal therapeutic administration in pain control
指導教授:呂平江楊寧正楊寧正引用關係
指導教授(外文):Lyu Ping ChiangYang Lin Chang
學位類別:博士
校院名稱:國立清華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:英文
論文頁數:51
中文關鍵詞:脊管內疼痛控制第二型環氧合成酶弗氏完全佐劑脊髓腫瘤
外文關鍵詞:Intrathecalpain controlcyclooxygenase-2complete Freund's adjuvantspinal tumor
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中文摘要
非類固醇消炎性藥品被開發成為臨床上治療疼痛的常用藥物,它們的藥物作用機轉主要是透過抑制COX (cyclooxygenase) 酵素。而COX酵素的作用是將arachidonic acid轉換成prostagladins,這些代謝產物就在發炎過程中參予很關鍵的角色。雖然在醫學和製藥工業不斷的開發,然而給藥的治療方式未有重大的改革,其中最大的限制就是沒有辦法將藥物濃度集中在需要治療的位置,因此必須給予大量的濃度以達到治療位置所需要的治療濃度。本實驗在大白鼠身上利用脊髓腔內(intrathecal;IT)給藥,將非類固醇消炎性藥品安全穩定送到特定的位置,抑制complete Freund’s adjuvant (CFA) 所引起的發炎疼痛反應。我們發現脊髓腔內給予非類固醇消炎性藥品會提昇COX-2的表現,因此推論在本動物的發炎止痛模式,抑制抑制抑制脊髓中PGE2活性可能會誘導COX-2的表現。
根據’世界衛生組織’的止痛藥階梯,對於溫和或中度疼痛,通常用非麻醉的止痛藥物來治療,就是非類固醇消炎性藥品及acetaminophen;但對於中重度的疼痛,到目前為止,類嗎啡止痛藥物仍然是對病患最有效的止痛藥物。然而,類嗎啡止痛藥物所帶來的耐藥性與成癮性,導致病人不敢使用止痛藥而無謂地忍受疼痛。近年來,由於疼痛過程中的分子機轉逐漸被發現,以細胞或基因治療的模式也逐漸被開發出來,本實驗進一步嘗試建立一細胞治療的模式,將腦垂體腺瘤細胞(GH3 cells)注射到大白鼠脊髓腔內,GH3細胞有類似chromaffin 細胞具有止痛的效果,藉著綠螢光蛋白的表現作為追蹤指標並評估GH3細胞在脊髓腔對疼痛控制的效果。然而實驗結果發現GH3細胞會在注射的位置產生腫瘤,經過組織切片免疫染色分析的鑑定確定是注射的GH3細胞長出的腫瘤,這個結果顯示細胞治療還是需要被包埋在合適的半透膜,解決腫瘤產生的問題後,才能安全地發揮其基因治療的功用。不過,GH3細胞在脊髓腔內所產生的腫瘤提供我們一個很合適的動物模式,來研究中樞神經的腫瘤病理問題以及腫瘤所造成的疼痛之控制。
Abstract
Nonsteroidal anti-inflammation drugs (NSAIDs) are developed as common analgesics for various clinical pain treatments. The mechanism of NSAIDs to suppress inflammation is to inhibit cyclooxygenase (COX) enzymes. The COX enzymes are required for conversion of arachidonic acid to prostagladins (PGs) and their metabolites play pivotal roles in inflammation processes. Despite the progress in medicine and pharmaceutics, drug administrations have less obvious variation and improvement. Limitation of the traditional administrations is that the applied drugs cannot be concentrated in a specific area within a specific organ. Therefore, high dosage is required for efficient curable concentration. In this thesis, IT (intrathecal) administration of NSAIDs in rats relieved thermal hyperalgesia through blockade of PGE2; however, it resulted in a significant short-term increase in spinal COX-2 expression.
According to the WHO analgesic ladder, nonopioid drugs, including NSAIDs and acetaminophen, are recommended for patients with mild to moderate pain; whereas, opioids remain the most efficient pharmaceutical agents for patients with moderate to severe pain. However, drug tolerance and addiction deprive patients of the benefits of opioids and thus causing needless misery. Recently, based on the studies of molecular events in pain processing, engineering cell transplantation and gene therapy are exploited as new treatment strategies. In this study, we developed a model of cell transplantation using pituitary adenoma GH3 cells injected into rat spinal cord intrathecally. GH3 cells also possess similar antinociceptive properties to chromaffin cells. In the model, green fluorescernt protein was transfected into GH3 cells as a trace marker and the antinociceptive effects of GH3 cells in spinal cord were evaluated. However, tumor mass was developed near the IT administrated site and the histopathologic results demonstrated that the tumor was resulted from the injection of the GH3 cells. The present data implied that encapculation of the engineered tumor cells in a semi-permeable membrane is necessary to avoid tumor formation and then to exert therapeutic functions safely. Nevertheless, this novel subarachnoid tumor can be created consistently in rats and mimic pathological conditions of human spinal tumor, thereby may be useful for pathophysiological studies and development for pain control in spinal tumor.
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