臺灣博碩士論文加值系統

Hemorphins 屬於非典型內生性類鴉片胜肽，經由 hemoglobin 之 β 鏈被切斷所形成之片段。在中樞神經系統中，hemorphins 以 LVV-hemorphin 7 (LVV-H7) 的濃度最高，其可結合於類鴉片 μ 受體而作為類鴉片受體致效劑，近來亦有學者提出 LVV-H7 也可作用於 insulin-regulated aminopeptidase 而產生抑制其活性之作用。在臨床上，同化類固醇的使用可增加血中 hemoglobin 濃度，曾經長期使用同化類固醇者，也被發現日後容易有類鴉片濫用之情況。因此我們推測同化類固醇之濫用，可能使得 LVV-H7 的生成增加進而影響中腦邊緣多巴胺系統較為敏感化。在本次實驗中，我們評估大鼠慢性給予同化類固醇後，對嗎啡酬賞作用之影響及其與 LVV-H7 之相關性。由我們的實驗結果得知，LVV-H7 可能不影響酬賞作用之神經迴路或者因 LVV-H7 抑制大鼠活動率之表現而使得在動物行為模式中無法觀察到酬賞作用之產生；然而，LVV-H7 造成活動率下降之機轉仍尚未明瞭，需進一步之研究。此外，我們的結果發現大鼠慢性給予同化類固醇後造成原先不產生酬賞作用之低劑量嗎啡，卻產生顯著之酬賞作用。然而，給予同化類固醇同時給予 anti-LVV-H7 antiserum，沒有阻斷同化類固醇所誘導之低劑量嗎啡對大鼠酬賞作用，因此我們排除 LVV-H7 與同化類固醇會加強嗎啡對大鼠酬賞作用有關。此外，我們測得慢性給予同化類固醇對血清中 LVV-H7 濃度之影響，儘管沒達到統計上顯著差異，但是我們結果顯示慢性給予同化類固醇後，LVV-H7 濃度有增加之趨勢。我們的推論與臨床觀察結果一致，慢性同化類固醇給予可能會增加嗎啡依賴性產生之可能性，但此作用與血清中 LVV-H7 濃度增加無關。因此，同化類固醇引起中腦邊緣多巴胺路徑之敏感化可能是其它因素的改變所致。

Hemorphins, hydrolysate of the β-chain of hemoglobin, were one kind of atypical endogenous opioid peptides. Among the hemorphins, LVV-hemorphin 7 (LVV-H7) was recognized to be the most abundant LVV-H7 in the CNS. LVV-H7 was shown to bind to μ-opioid receptors and to act as an agonist. Recently, LVV-H7 was proved to be an inhibitor of insulin-regulated aminopeptidase. In clinics, subchronic administration of anabolic androgenic steroids (AASs) induced the synthesis of erythrocytes and increased hemoglobin concentrations. Patients with a history of AAS abuse were more susceptible to turning to opioid abuse. This was speculated to be partially attributed to the sensitization of mesolimibic dopaminergic pathway by LVV-H7. In the present study, we investigated the possible mechanism underlying the effect of chronic AAS administration on morphine rewarding effect and its correlation with LVV-H7 in rats. Our results showed that either LVV-H7 may not sensitize the rewarding neural circuits or its inhibition on locomotor activity could mask the rewarding effect in our behavioral model. Nevertheless, the finding of LVV-H7 to decrease locomotor activity is novel, although the underlying mechanism requires further investigation. In addition, the chronic nandrolone pre-treatment induced a significant rewarding effect of low dose morphine, which could not induce any rewarding in control rats. However, co-administration of anti-LVV-H 7 antiserum with AAS did not block the effect of AAS on the rewarding induced by low dose of morphine. This may rule out the possibility of the involvement of LVV-H7 in the action of AAS to intensify the sensation of morphine rewarding. Moreover, we measured the serum level of LVV-H7 in response to chronic AAS administration. The results showed a mild increase of LVV-H7 caused by chronic AAS, although it did not reach the statistical significance. In consistence with the clinical observations, we may conclude that chronic administration of AAS could increase the liability to morphine dependence, but this effect may possibly be not related to the elevation of LVV-H7 in serum. The sensitization of mesolimbic dopaminergic pathway could be due to the change of the other factors by AAS.

總目錄 I
正文目錄 II
圖目錄 VI
表目錄 VIII
縮寫對照表 IX
中文摘要 X
英文摘要 XII
第一章、緒言 1
第二章、實驗目的 14
第三章、材料與方法 15
第四章、實驗結果 38
第五章、討論 39
第六章、結論 44
附圖 45
參考文獻 58

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