Lutz Pierre-Eric, Almeida Daniel, Filliol Dominique, Jollant Fabrice, Kieffer Brigitte L, Turecki Gustavo
McGill Group for Suicide Studies, Douglas Mental Health Research Centre, McGill University, 6875 LaSalle Boulevard, Verdun, Montréal, QC, Canada.
Centre National de la Recherche Scientifique, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives UPR3212, Strasbourg, France.
Neuropsychopharmacology. 2021 Apr;46(5):920-927. doi: 10.1038/s41386-021-00974-y. Epub 2021 Feb 2.
The mu opioid receptor (MOR) is a G protein-coupled receptor that plays an essential role in reward and hedonic processes, and that has been implicated in disorders such as depression and addiction. Over the last decade, several brain imaging studies in depressed patients have consistently found that dysregulation of MOR function occurs in particular in the anterior insular cortex, an important brain site for the perception of internal states and emotional regulation. To investigate molecular mechanisms that may underlie these effects, here we assessed genetic polymorphisms, expression, and functional G-protein coupling of MOR in a large post-mortem cohort (N = 95) composed of depressed individuals who died by suicide, and healthy controls. Results indicated that depression, but not comorbid substance use disorder or acute opiate consumption, was associated with increased MOR activity. This effect was partly explained by a specific increase in expression of the inhibitory alpha G-protein subunit GNAI2. Consistent with previous neuroimaging studies, our findings support the notion that enhanced endogenous opioidergic tone in the anterior insula may buffer negative affective states in depressed individuals, a mechanism that could potentially contribute to the antidepressant efficacy of emerging opioid-based medications.
μ阿片受体（MOR）是一种G蛋白偶联受体，在奖赏和享乐过程中起关键作用，并且与抑郁症和成瘾等疾病有关。在过去十年中，多项针对抑郁症患者的脑成像研究一致发现，MOR功能失调尤其发生在脑岛前叶皮质，这是一个对感知内部状态和情绪调节很重要的脑区。为了探究这些效应背后的分子机制，我们在此评估了一个由自杀身亡的抑郁症患者和健康对照组成的大型尸检队列（N = 95）中MOR的基因多态性、表达及功能性G蛋白偶联情况。结果表明，抑郁症而非共病物质使用障碍或急性阿片类药物使用与MOR活性增加有关。这种效应部分由抑制性α G蛋白亚基GNAI2表达的特异性增加所解释。与先前的神经影像学研究一致，我们的研究结果支持这样一种观点，即脑岛前叶内源性阿片能张力增强可能缓冲抑郁症患者的负性情绪状态，这一机制可能有助于新型阿片类药物的抗抑郁疗效。
