類鴉片耐受性：麩胺酸與乙型休止素間的協調

Opioid Tolerance: Is There a Dialogue Between Glutamate and β-arrestin?

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，可透過蛋白激酶C去調控μ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，μ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，給予蛋白激酶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，蛋白激酶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。蛋白激酶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，我們認為蛋白激酶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。

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 β-opioid tolerance and associated abnormal pain sensitivity. Many NMDA receptor antagonists had been demonstrated to regulate morphine tolerance development. In the NMDA-mediated intracellular mechanisms of opioid tolerance, protein kinase C (PKC) modulates β-opioid receptor activation. Besides, the opioid receptor desensitization involves phosphorylation of receptors and subsequent binds to β-arrestin. In knockout mice, lacking β-arrestin-2, desensitization of β-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 β-arrestin-2 knock-out, but not wild-type mice. These findings indicate that, in the absence of β-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, β-arrestin-2 also influences PKC-induced opioid receptor desensitization. PKC may play an important role to coordinate these factors which regulate opioid tolerance.