Ketamine（K他命）是一種短效解離性麻醉劑，因具有引發幻覺之副作用，導致增加其在夜店及派對中遭到非法的使用。臨床上，K他命的濫用與許多下泌尿道功能障礙有關，而一些長期藥物濫用之案例亦發現K他命可能會導致膀胱容積減少及具不可逆病理變化的出血性膀胱炎。然而造成這些嚴重副作用的機制仍未清楚。因此，本研究以K他命成癮的大鼠為動物模式探討病理變化及泌尿道膀胱受損的機制。大鼠分為對照組、K他命刺激14天及K他命刺激28天三組，K他命（25 mg / kg / day）採腹腔注射給予，而對照組則給予生理食鹽水。除了進行膀胱容積壓力檢查及測定膀胱僵硬參數外，亦收集膀胱組織進行蛋白質分析和免疫組織化學染色。結果顯示相較於對照組，K他命刺激後會顯著增加排尿壓力並降低膀胱容積，此變化在K他命刺激28天後則更顯著。K他命刺激也會顯著降低膀胱順應性及增加儲存期膀胱的非排尿收縮，由免疫螢光染色顯示K他命刺激後之神經絲顯著的減少，證實K他命的神經毒性，而尿路上皮、次尿路上皮與平滑肌層經 TUNEL 染色也呈現多重退化細胞的瀰漫，另西方墨點法分析亦顯示K他命刺激會增加膀胱中iNOS 、 eNOS 和 COX-2 的表現量。綜合而言慢性暴露於低劑量的K他命會影響細胞的存活及損害組織的形態，進而導致神經網路障礙及改變膀胱的排尿反射。

Ketamine is a short-acting dissociative anesthetic and its hallucinogenic side effects have led to increased illicit use among night clubs and party goers. Clinically, ketamine abuse is associated with severe lower urinary tract dysfunction and reduced bladder capacity and hemorrhagic cystitis with irreversible pathological changes which may develop in some cases of long-term drug abuse. Up to now, the mechanisms causing these severe side-effects are still not clear. Herein, a novel ketamine addiction rat model was used to examine the pathological changes and explore the mechanisms of urinary bladders destruction. Rats were divided into groups of control, ketamine injection 14 days and 28 days. Ketamine injection (25 mg/kg/day) was given intraperitoneally while normal saline was given for control group. In vivo isovolumetric cystometrography studies were performed, bladder stiffness parameters were measured, and the bladder tissues were collected for protein analysis and immunohistochemical staining. Ketamine treatment significantly increased micturition pressure but decreased bladder capacity in rats. Ketamine treatment also significantly decreased bladder compliance and increased bladder non-voiding contraction during storage phase. Immunofluorescence studies showing significantly decreased neurofilament staining after ketamine injection 28 days confirmed the neurotoxicity of ketamine. TUNEL staining also showed multiple degenerating cells diffusely distributed in urothelium, suburothelium, and smooth muscle layers in ketamine injected rats. Western blotting demonstrated ketamine injection increased bladder iNOS, eNOS and COX-2 expression. It is concluded that chronic exposure to low, subanesthetic concentrations of ketamine could affect cell survival and impair neuronal morphology which subsequently led to dysfunction of neural networks and altered bladder micturation reflex.

中文摘要 I
英文摘要 . II
目錄 .. IV
第 一 章 前言與文獻回顧 01
一、K他命 01
二、潰瘍性膀胱炎 03
三、環氧化酶-2 04
四、 一氧化氮合成酶 05
第 二 章 研究方法與材料 08
一、實驗動物 08
二、動物設計 08
三、尿路動力學檢查 09
四、尿液中K他命與去甲K他命的分析 10
五、組織化學染色分析 10
六、細胞凋亡分析 11
七、免疫組織染色 12
八、西方墨點法 12
九、統計分析 15
第 三 章 結果 16
一、K他命刺激對大鼠尿動力學參數之影響 16
二、大鼠尿液與血清中K他命及其代謝產物之濃度 16
三、K他命刺激對大鼠腎功能和肝功能之影響評估 17
四、K他命刺激引發膀胱損傷之組織學變化 18
五、K他命刺激後TGFβ促進第一型膠原蛋白和纖維連接蛋白 18
六、K他命刺激對細胞凋亡之影響 19
七、K他命刺激後COX-2和NOS之表現量變化 20
八、泌尿道膀胱中COX-2與巨噬細胞和淋巴細胞共定位標記 21
九、K他命刺激能顯著改變膀胱的神經功能 22
十、K他命刺激對膀胱中2 , 4 -dinitrophenol（DNP）與硝基酪胺酸含
量之影響 22
第 四 章 討論與結論 23
第 五 章 參考文獻 26
第 六 章 圖表與附錄 30

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