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研究生:蕭翔仁
研究生(外文):Hsiao Hsiang-Jen
論文名稱:探討U-50,488對嗎啡耐藥性與依賴性之影響及可能的機轉
論文名稱(外文):Study of the effect and mechanism of U-50,488 in morphine tolerance and dependence
指導教授:陶寶綠
指導教授(外文):Tao Pao-Luh
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2001
畢業學年度:90
語文別:中文
論文頁數:84
中文關鍵詞:嗎啡耐藥性
外文關鍵詞:MorphineU-50488Tolerance
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嗎啡一種是用於臨床上解除手術後及癌症疼痛的強而有效的止痛劑,但長期使用嗎啡郤會有耐藥性及依賴性的產生。嗎啡的依賴性又可被區分為生理的依賴性和心理的依賴性。生理的依賴性可以利用一些藥物如:clonidine 及抗焦慮劑來減輕症狀,但是對於心理的依賴性,至目前仍無有效的藥物來治療。在具有毒癮的患者身上可能會產生戒斷症狀並渴求藥物,但在一般臨床使用劑量下,嗎啡並不易產生心理的依賴性,而吸毒者產生之嚴重的心理依賴性,很可能是吸毒者難以戒除毒癮的主要原因之一。
之前我們的實驗室研究發現κ-受體致效劑,U-50,488 可有效地抑制嗎啡的耐藥性。所以本論文研究主題便是要討探 U-50,488 對嗎啡的報償行為 (rewarding) 及依賴性有何作用。在動物行為實驗中,我們採用 conditioned place preference (CPP),CPP 是一種最常取代自主性給藥 (self-administration),用以評估動物覓藥行為的實驗方法。我們使用雄性SD大鼠為實驗動物,並以CPP 及經由 naloxone 誘發的戒斷症狀分別檢測其心理及生理的依賴性。由實驗結果發現 U-50,488 (8 mg/kg) 幾乎可完全抵消嗎啡所產生的CPP作用,並可減輕部份的戒斷症狀。而在另外的行為實驗中亦發現,U-50,488 也可以部份抑制嗎啡之止痛耐藥性及其對活動性 (locomotor activity) 之致敏性。此外,我們使用了微透析的技術去檢測阿控伯核(nucleus accumbens) 殼部 (shell) 細胞外多巴胺的活性,並藉以探討 U-50,488 對嗎啡報償行為之神經化學變化之影響。實驗結果顯示急性給予嗎啡會使阿控伯核殼部區域內多巴胺的代謝物增加,而此作用可被 U-50,488減弱。根據以上的實驗結果顯示,我們推斷U-50,488 可能具有減輕嗎啡生理及心理依賴性之作用,此類藥物並在臨床治療上具有一定之潛力。

Morphine is one of the most effective analgesics to treat postoperative pain or cancer pain in clinics. However, the utilization of morphine was limited due to the development of tolerance and dependence after its continuous use. Morphine dependence could be subdivided into physical dependence and psychological dependence. The physical dependence could be partially suppressed by some drugs, such as clonidine and anti-anxiety agents. However, there is no drug able to effectively prevent the psychological dependence. Having abused opioid drugs in the past, patients may experience withdrawal signs and drug craving, once stop using the drug. Although the psychological dependence is rarely seen in patients under therapeutic dosage, it has been recognized as the most important factor of relapse for morphine addicts.
In our previous study, we found that the κ-opioid receptor agonist, U-50,488 could partially prevent the development of antinociceptive tolerance to morphine in rats. Therefore, the aim of the present study is to further investigate the possible effects of U-50,488 on morphine rewarding and dependence. To investigate the possible psychological effects of morphine, a number of experimental methods have been developed and employed. Among these methods, conditioned place preference (CPP) test was proved to be a practically useful alternative to self-administration for the assessment of drug-seeking behavior. In our behavioral experiments using male Sprague-Dawley rats (250-300g), CPP and naloxone (4 mg/kg, i.p.)-precipitated withdrawal were employed to examine psychological and physical dependence respectively. The results revealed that U-50,488 (8 mg/kg, i.p.) could almost completely abolish the morphine (10 mg/kg, i.p.)-induced CPP. In addition, U-50,488 was also found to attenuate morphine-induced behavioral sensitization of locomotor activity and attenuate certain naloxone-precipitated withdrawal signs. To investigate the neurochemistry of morphine rewarding in correlation to its dependence, we used the technique of microdialysis to determine the change of extracellular dopamine metabolites in the shell of nucleus accumbens (NAc). In consistent with the other reports, the acute administration of morphine could result in an increase of dopamine metabolites in NAc. The morphine-induced increase could be significantly attenuated by U- 50488. According to the present results, U-50488 (8 mg/kg, i.p.) may possess an ability to prevent morphine-induced physical and psychological dependence, which could be of great therapeutic potential.

目錄……………………………………………………………………….Ⅰ
表次與圖次……………………………………………………………….Ⅱ
中文摘要………………………………………………………………….Ⅳ
英文摘要………………………………………………………………….Ⅵ
第一章 緒論……………………………………………………………..1
第二章 實驗目的……………………………………………………….16
第三章 實驗材料與方法……………………………………………….18
第四章 實驗結果……………………………………………………….32
第五章 討論…………………………………………………………….41
第六章 總結…………………………………………………………….53
附圖……………………………………………………………………….55
附表……………………………………………………………………….77
參考文獻………………………………………………………………….78
表目錄與圖目錄
Table 1. Individual scores of the naloxone-precipitated morphine withdrawal signs……………………………………………77
Fig 1. The chemical structure of morphine………………………55
Fig 2. Coronal plates from the atlas of Paxions and Watson (1998) depiciting the rostrocaudal extent of the target region for cannulae implant into the shell region of nucleus accumbens……………………………………………56
Fig 3. An example of the HPLC profile of DOPAC, 5-HIAA and HVA before drug injection (basal level)………………………………57
Fig 4. An example of the HPLC profile of DOPAC, 5-HIAA and HVA after morphine injection for 165 minutes………………………58
Fig 5. The effect of U-50,488 on morphine-induced conditioned place preference (CPP)………………………………………………59
Fig 6. The effect of U-50,488 on the development of morphine tolerance to antinociception in rats……………………………60
Fig 7. The effect of U-50,488 on the development of morphine-induced behavioral sensitization of total activity…………61
Fig 8. The effect of U-50,488 on the development of morphine-induced behavioral sensitization of ambulatory activity.…62
Fig 9. Basal concentrations (nM) of DOPAC, HVA and 5-HIAA for the control group on Day 1 and Day 4 ……………………………63
Fig 10. Time-dependent change of DOPAC in the shell of nucleus accumbens after drug administration on day 1…………………64
Fig 11. Time-dependent change of DOPAC in the shell of nucleus accumbens after drug administration on day 4…………………65
Fig 12. Time-dependent change of HVA in the shell of nucleus accumbens after drug administration on day 1…………………66
Fig 13. Time-dependent change of HVA in the shell of nucleus accumbens after drug administration on day 4…………………67
Fig 14. Time-dependent change of 5-HIAA in the shell of nucleus accumbens after drug administration on day 1…………………68
Fig 15. Time-dependent change of 5-HIAA in the shell of nucleus accumbens after drug administration on day 4…………………69
Fig 16. A bar graph presenting the area under curve (AUC) of the microdialysis curves (0 to 225 min; as show in Fig. 10, 11) of DOPAC in the shell of nucleus accumbens……………………70
Fig 17. A bar graph presenting the area under curve (AUC) of the microdialysis curves (0 to 225 min; as show in Fig. 12, 13) of HVA in the shell of nucleus accumbens………………………71
Fig 18. A bar graph presenting the area under curve (AUC) of the microdialysis curves (0 to 225 min; as show in Fig. 14, 15) of 5-HIAA in the shell of nucleus accumbens……………………72
Fig 19. A bar graph showing the basal concentrations (nM) of DOPAC, HVA and 5-HIAA for the morphine group on Day 1 and Day 4………………73
Fig 20. A bar graph showing the basal concentrations (nM) of DOPAC, HVA and 5-HIAA for the U-50,488 group on Day 1 and Day 4………………74
Fig 21. A bar graph showing the basal concentrations (nM) of DOPAC, HVA and HVA for the U-50,488 group on Day 1 and Day 4………………75
Fig 22. A model for the modulation of mesolimbic A10 neurons by endogenous opioid systems……………………………………………76

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