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題 名 | Opioid Tolerance: Is There a Dialogue between Glutamate and β-arrestin?=類鴉片耐受性:麩胺酸與乙型休止素間的協調 |
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作 者 | 焦玉中; 汪志雄; | 書刊名 | 麻醉學雜誌 |
卷 期 | 42:2 2004.06[民93.06] |
頁 次 | 頁93-101 |
分類號 | 418.224 |
關鍵詞 | 類鴉片藥物; 藥物耐受性; 麩胺酸鹽; 休止素; 蛋白激酶C; Drug tolerance; Analgesics; Opioid; Glutamates; Arrestin; Protein kinase C.; |
語 文 | 英文(English) |
中文摘要 | 類鴉片藥物在臨床上被用來做為止痛劑已有很長的時間。但是使用類鴉片藥物會產生耐藥性, 進而使藥效降低, 然而持續增加劑量又會對病患不利, 於是形成臨床上一個令人困擾的問題。類鴉片耐藥性的產生機制相當複雜, 包括了許多細胞內與細胞外的控制因子。麩胺酸鹽是一個很重要的中樞神經傳導物質, 它透過專一受器的作用, 在神經細胞內引發一連串的反應而調控類鴉片耐藥性的產生。以往的實驗證實NMDA 受器參與由嗎啡引起的耐藥性與痛覺過敏。許多NMDA 受器的拮抗劑也具有調控嗎啡耐藥性的作用。在由NMDA 受器引發的細胞內反應中, 可透過蛋白激C去調控鴉片受器的活化。而在類鴉片受器本體方面, 受器的去敏感作用必須仰賴受器本體的磷酸化作用與乙型- 休止素-2 的作用。若是觀察去乙型- 休止素-2 基因表現的小鼠, 在長期給予嗎啡後, 鴉片受器的去敏感作用無法產生, 此種動物也比較不會產生類鴉片耐藥性。當去乙型- 休止素-2 基因表現的小鼠發生類鴉片耐藥性後, 給予蛋白激C 的抑制劑能夠完全消除類鴉片耐藥性, 但在正常小鼠中則無法消除類鴉片耐藥性。這顯示在缺乏乙型- 休止素-2 的情形下, 蛋白激C對鴉片受器的調控便顯得格外重要。乙型- 休止素-2 在細胞內掌控了鴉片受器去敏感作用的進行, 並且可能控制其他影響因子的作用。蛋白激C受到NMDA 受器的影響而活化, 而類鴉片受器的去敏感作用又受到乙型-休止素-2 的管制, 因此, 我們認為蛋白激C在影響類鴉片耐藥性形成的麩胺酸鹽和乙型- 休止素-2 等的細胞內因子具有居中協調的角色。 |
英文摘要 | Opioids are widely used as analgesics in clinical pain management for decades. However, opioid tolerance is a serious problem which limits their usefulness. The mechanisms of opioid tolerance are complex which involve many regulatory factors. Glutamate is an important extracellular neurotransmitter which activates glutamate receptor and induces a series of signal transduction to regulate the development of opioid tolerance. Previous studies have indicated an involvement of NMDA receptors in the development of -opioid tolerance and associated abnormal pain sensitivity. ManyNMDA receptor antagonists had been demonstrated to regulate morphine tolerance development. In the NMDA-mediated intracellular mechanisms of opioid tolerance, protein kinase C (PKC) modulates -opioid receptor activation. Besides, the opioid receptor desensitization involves phosphorylation of receptors and subsequent binds to -arrestin. In knockout mice, lacking -arrestin-2, desensitization of -opioid receptor did not occur after chronic morphine treatment, and these animals also failed to develop antinociceptive tolerance. Moreover, morphine tolerance can be completely reversed with a low dose of the classical PKC inhibitor chelerythrine in the -arrestin-2 knock-out, but not wild-type mice. These findings indicate that, in the absence of -arrestin-2, contributions of PKC-dependent regulatory system would become apparent. In summary, PKC is regulated by NMDA receptors to affect the development of opioid tolerance, -arrestin-2 also influences PKCinduced opioid receptor desensitization. PKC may play an important role to coordinate these factors which regulate opioid tolerance. |
本系統中英文摘要資訊取自各篇刊載內容。