Endogenous opioid peptides in the amygdala regulate many of our behaviors and emotional responses. In particular, the endogenous opioid enkephalin plays a significant role in regulating amygdala activity, but its action is strongly limited by peptidases, which degrade enkephalin into inactive fragments. Inhibiting peptidases may be an attractive method to enhance endogenous opioid signaling; however, we do not know which specific peptidase(s) to target. Using inhibition of glutamate release onto the intercalated cells of the amygdala as an assay for enkephalin activity, we applied specific peptidase inhibitors to determine which peptidase(s) regulate enkephalin signaling in this region. Thiorphan (10 μM), captopril (1 μM), or bestatin (10 μM) were used to inhibit the activity of neprilysin, angiotensin-converting enzyme, or aminopeptidase N, respectively. In rat brain slices containing the intercalated cells, we found that inhibition of glutamate release by a submaximal concentration of enkephalin was doubled by application of all three peptidase inhibitors combined. Then, we tested inhibitors individually and found that inhibition of neprilysin alone could enhance enkephalin responses to the same extent as inhibitors of all three peptidases combined. This indicates neprilysin is the predominant peptidase responsible for degrading enkephalins in the intercalated cells of the amygdala. This differs from the striatum, locus coeruleus, and spinal cord, where multiple peptidases metabolize enkephalin. These data highlight the importance of knowing which specific peptidase(s) control opioid actions in the relevant neural circuit and how they change in disease states to allow rational choices of drugs targeting the specific peptidase of interest.

中文翻译：

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脑啡肽酶控制杏仁核插层细胞中神经肽的突触活性。

杏仁核中的内源性阿片肽调节我们的许多行为和情绪反应。特别地，内源性阿片样脑啡肽在调节杏仁核活性中起着重要作用，但是其作用受到肽酶的强烈限制，肽酶将脑啡肽降解为非活性片段。抑制肽酶可能是增强内源性阿片样物质信号传导的有吸引力的方法。但是，我们不知道靶向哪些特定的肽酶。使用抑制谷氨酸释放到杏仁核的插层细胞上作为脑啡肽活性的测定方法，我们应用了特定的肽酶抑制剂来确定哪些肽酶调节该区域的脑啡肽信号传导。噻吗啡（10μM），卡托普利（1μM）或贝他汀（10μM）用于抑制中性溶酶，血管紧张素转化酶或氨肽酶N的活性，分别。在包含插层细胞的大鼠脑切片中，我们发现通过同时使用所有三种肽酶抑制剂，亚最大浓度的脑啡肽对谷氨酸释放的抑制作用增加了一倍。然后，我们分别测试了抑制剂，发现单独抑制neprilysin可以增强脑啡肽的反应，其程度与所有三种肽酶抑制剂的总和相同。这表明脑啡肽酶是主要的肽酶，负责降解杏仁核插层细胞中的脑啡肽。这不同于纹状体，蓝斑和脊髓，在脊髓中多个肽酶代谢脑啡肽。