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研究生:陳慶明
研究生(外文):Chen CM
論文名稱:內嗎啡在大鼠上脊髓的抗神經痛及酬賞作用
論文名稱(外文):SUPRASPINAL ANTI-ALLODYNIA AND REWARDING EFFECT OF ENDOMORPHINS IN RATS
指導教授:陶 寶 綠
指導教授(外文):Tao PL
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:2002
畢業學年度:90
語文別:中文
中文關鍵詞:內嗎啡
相關次數:
  • 被引用被引用:1
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內嗎啡-1(endomorphin-1, EM-1)和內嗎啡-2(endomorphin-2, EM-2)是在1997年由Zadina等人,首先在牛腦分離出來,為具有高度的m-類鴉片受體致效劑。在1999年Przewlocka等人研究指出EM-1和EM-2經由脊椎給藥(i.t.),不但具有抗神經痛,如”觸感痛”(allodynia)的能力,而且效果比嗎啡還好。最近的研究也指出EM-1和EM-2的止痛作用(antinociception)可以被naloxonazine (選擇性m1-類鴉片受體拮抗劑)所抑制。 嗎啡的止痛作用主要經由m-類鴉片受體,但具有心理性的酬賞作用,而且能增加阿控伯核外殼區胞外的多巴胺濃度,這與嗎啡的成癮性可能有關。
本實驗之目的係探討EM-1和EM-2在大鼠脊髓以上的大腦(supraspinal)是否亦具有抗神經痛的作用,並研究其作用機轉是否透過m-類鴉片受體,或m1-類鴉片受體。此外並探討EM-1和EM-2在大鼠是否具有酬賞作用(rewarding),其機轉如何。
在神經痛的部份,我們使用冰水測試神經痛的反應(cold-water allodynia test)來測試endomorphins在抗神經痛的反應。在成癮性方面,我們使用環境喜好試驗(conditioned place preference , CPP)來測試endomorphins的酬賞作用,並且使用微透析實驗 (microdialysis)探討給予endomorphins後阿控伯核外殼區胞外神經傳遞物質的變化,以佐證CPP方面的實驗。
結果發現在抗神經痛方面,大鼠由腦室給予EM-1 (15 mg)或EM-2 (15 mg)均具有抗神經痛之作用,且EM-1的作用時間較EM-2長;EM-1及EM-2之止痛效果皆可以被naltrexone (15 mg, i.c.v.)或naloxonazine (15 mg, i.c.v.)所拮抗。
在酬賞作用方面,EM-1和EM-2在15 mg經由i.c.v給藥均不具有顯著的酬賞作用,但EM-2增加劑量至30 mg經由腦室給藥,則具顯著酬賞作用。
由微透析實驗 (microdialysis)的結果,發現EM-1 (15 mg, i.c.v.)並不會增加在阿控伯核殼區DOPAC、HVA或5-HIAA的濃度;EM-2 (30 mg, i.c.v.)則會增加阿控伯核殼區DOPAC或DOPAC + HVA的濃度,但對於5-HIAA的濃度並無影響。
EM-1或EM-2經由腦室給藥,均具有抗神經痛(觸感痛)的效果,且EM-1比EM-2作用時間更長,其作用主要經由m1類鴉片受體。此外,EM-1和EM-2在(15 mg, i.c.v.)的止痛劑量下可能不具有酬賞性,因此成癮性可能較嗎啡小。

Two potent endogenous opioid peptides, endomorphin-1 (EM-1) and —2 (EM-2), which are selective m-opioid agonists, have been recently isolated from bovine and human brain. These endomorphins have been shown to produce a potent anti-allodynic effect at spinal level. Endomorphins are considered as endogenous ligands for the m-opioid receptor. A prominent characteristic of m-opioid agonists is their ability to elicit strong rewarding effects. Therefore we further investigated their supraspinal anti-allodynic effects and rewarding effects in the present study.
In a neuropathic pain model (sciatic nerve crushing in rats), EM-1 and EM-2 (15 mg, i.c.v.) showed significant effects in the cold-water allodynia test. EM-1 is more potent than EM-2. Naltrexone (15 mg) or naloxonazine (15 mg) completely blocked the effects of both EM-1 and EM-2. In a conditioned place preference test, EM-2 at the dose of 30 mg has been shown to produce positive rewarding effects whereas EM-1 or EM-2 at the dose of 15 mg had no effect. EM-2 (30 mg) also increased the extracellular concentration of (DOPAC + HVA) at nucleus accumbens shell, but not EM-1 (15 mg).
The present results suggest that the endomorphin-1 is more potent than endophin-2 in anti-neuropathic pain by supraspinal administration. These anti-allodynia effects of endomorphins are possible via m1-opioid receptors. In the conditioned place preference (CPP) test, EM-1 (15mg) and EM-2 (15 mg) did not show any rewarding effect. However, EM-2 produced a significant rewarding effect at the higher dose of 30 mg (i.c.v.). In summary, EM-1 (15 mg) has good supraspinal anti-allodynic effect through the activation of m1-opioid receptors and may be with less tendency to induce psychological dependence. In contrast, EM-2 may be less effective in anti-allodynia and more likely to produce psychological dependence.

目錄……………………………………………………………………. Ⅰ
圖次……………………………………………………….…………… Ⅱ
中文摘要………………………………………………….…………… Ⅲ
英文摘要……………………………………………….……………… Ⅴ
第一章、緒言………………………………………………………… 1
第二章、實驗目的……………………………………………………. 16
第三章、實驗材料與方法……………………………………………. 17
第四章、實驗結果……………………………………………………. 29
第五章、討論………………………………………………..……….. 35
第六章、結論……………………………………………….………… 42
附圖………………………………………………………….………… 43
參考文獻……………………………………………………………… 53
圖次
(圖一)內嗎啡抗神經痛的時間與作用圖…………….……...…… 43
(圖二)抗神經痛中各組AUC的比較圖….………………………. 44
(圖三)正常大鼠,內嗎啡的CPP測試結果……………………… 45
(圖四)神經痛大鼠中,內嗎啡的CPP測試結果……………… 46
(圖五)腦室給予內嗎啡,在阿控伯核外殼區胞外DOPAC的濃
度百分比隨時間變化圖…………………………………… 47
(圖六)圖五中各組的AUC比較圖……………………………….. 48
(圖七)腦室給予內嗎啡,在阿控伯核外殼區胞外(DOPAC +
HVA)的濃度百分比隨時間變化圖……………………… 49
(圖八)圖七中各組的AUC比較圖………………………………. 50
(圖九)腦室給予內嗎啡,在阿控伯核外殼區胞外5-HIAA的濃度百分比隨時間變化圖,各組AUC的比較圖…………………51
(圖十) dopamine的代謝圖…………………………………………… 52

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