Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA.
Medical Scientist Training Program, University of Minnesota Medical School, Minneapolis, MN, USA.
Science. 2022 Mar 11;375(6585):1177-1182. doi: 10.1126/science.abl5130. Epub 2022 Feb 24.
Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced µ-opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but it led to a decrease in conditioned place preference caused by fentanyl administration and an enhancement of reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit while mitigating the risk of addiction.
血管紧张素转化酶（ACE）通过切割血管紧张素 I 产生血管紧张素 II 来调节血压。在大脑中，ACE 在纹状体组织中特别丰富，但 ACE 在纹状体回路中的功能仍知之甚少。我们发现 ACE 可降解小鼠伏隔核中的一种非传统脑啡肽七肽，Met-脑啡肽-Arg-Phe。ACE 抑制增强了 Met-脑啡肽-Arg-Phe 对 µ-阿片受体的激活，导致表达 Drd1 多巴胺受体的中脑投射神经元上谷氨酸释放的特定细胞类型的长时程抑制。全身 ACE 抑制本身并没有奖赏作用，但它导致芬太尼给药引起的条件性位置偏好减少，并增强了互惠的社会互动。我们的结果提出了一个诱人的前景，即中枢 ACE 抑制可以增强内源性阿片信号，从而获得临床益处，同时降低成瘾风险。
