Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY, 10029, USA.
Emcure Pharmaceuticals, Mumbai, India.
Cell Mol Neurobiol. 2021 Jul;41(5):1103-1118. doi: 10.1007/s10571-020-01015-w. Epub 2021 Jan 2.
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，从而调节许多情绪和生理反应。三种主要的内源性阿片肽，β-内啡肽、脑啡肽和强啡肽，分别来自三种主要前体：前阿黑皮素原、前啡肽原和前强啡肽原。我们采用基因敲除的方法，试图确定内源性阿片肽缺失是否会影响缺乏前啡肽原、β-内啡肽或两者的小鼠中阿片受体的表达或活性。由于基因敲除可能导致相关前体产生的肽水平发生代偿性变化，我们直接测量了缺乏前啡肽原、β-内啡肽或两者的动物大脑中的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，亮氨酸脑啡肽的水平显著降低，这表明前啡肽原是亮氨酸脑啡肽的主要来源。该数据还表明，缺乏β-内啡肽和/或前啡肽原不会导致前强啡肽原加工的代偿性变化。接下来，我们研究了内源性肽缺失对特定脑区阿片受体水平和活性调节的影响。我们还比较了雄性和雌性动物的受体水平和活性，并表明缺乏β-内啡肽和/或前啡肽原以区域和性别特异性的方式导致三种阿片受体的差异调节。这些结果表明，内源性阿片肽是大脑中阿片受体表达和活性的重要调节剂。
