Activation of μ, δ, and κ opioid receptors by endogenous opioid peptides leads to the regulation of many emotional and physiological responses. The three major endogenous opioid peptides, β-endorphin, enkephalins, and dynorphins result from the processing of three main precursors: proopiomelanocortin, proenkephalin, and prodynorphin. Using a knockout approach, we sought to determine whether the absence of endogenous opioid peptides would affect the expression or activity of opioid receptors in mice lacking either proenkephalin, β-endorphin, or both. Since gene knockout can lead to changes in the levels of peptides generated from related precursors by compensatory mechanisms, we directly measured the levels of Leu-enkephalin and dynorphin-derived peptides in the brain of animals lacking proenkephalin, β-endorphin, or both. We find that whereas the levels of dynorphin-derived peptides were relatively unaltered, the levels of Leu-enkephalin were substantially decreased compared to wild-type mice suggesting that preproenkephalin is the major source of Leu-enkephalin. This data also suggests that the lack of β-endorphin and/or proenkephalin does not lead to a compensatory change in prodynorphin processing. Next, we examined the effect of loss of the endogenous peptides on the regulation of opioid receptor levels and activity in specific regions of the brain. We also compared the receptor levels and activity in males and females and show that the lack of β-endorphin and/or proenkephalin leads to differential modulation of the three opioid receptors in a region- and gender-specific manner. These results suggest that endogenous opioid peptides are important modulators of the expression and activity of opioid receptors in the brain.

内源性阿片肽激活 μ、δ 和 κ 阿片受体导致许多情绪和生理反应的调节。三种主要的内源性阿片肽、β-内啡肽、脑啡肽和强啡肽由三种主要前体的加工产生：原阿片黑皮质素、脑啡肽原和强啡肽原。使用敲除方法，我们试图确定缺乏内源性阿片肽是否会影响缺乏脑啡肽原、β-内啡肽或两者的小鼠中阿片受体的表达或活性。由于基因敲除可通过补偿机制导致相关前体产生的肽水平发生变化，因此我们直接测量了缺乏脑啡肽原、β-内啡肽或两者的动物大脑中亮氨酸脑啡肽和强啡肽衍生肽的水平。我们发现，虽然强啡肽衍生肽的水平相对不变，但与野生型小鼠相比，Leu-脑啡肽水平显着降低，这表明前脑啡肽原是 Leu-脑啡肽的主要来源。该数据还表明，β-内啡肽和/或脑啡肽原的缺乏不会导致强啡肽原加工的补偿性变化。接下来，我们检查了内源性肽缺失对大脑特定区域阿片受体水平和活性调节的影响。我们还比较了男性和女性的受体水平和活性，并表明缺乏 β-内啡肽和/或脑啡肽原导致三种阿片受体以区域和性别特异性方式的差异调节。