Department of Psychiatry, University of Cincinnati, GRI E205 (ML: 0506), 2170 E Galbraith Road, Cincinnati, Ohio 45237, USA.
Endocrinology. 2010 Oct;151(10):4811-9. doi: 10.1210/en.2010-0285. Epub 2010 Aug 11.
Glucocorticoid hormones are secreted in response to stimuli that activate the hypothalamo-pituitary-adrenocortical (HPA) axis and self-regulate through negative feedback. Negative feedback that occurs on a rapid time scale is thought to act through nongenomic mechanisms. In these studies, we investigated fast feedback inhibition of HPA axis stress responses by direct glucocorticoid action at the paraventricular nucleus of the hypothalamus (PVN). Local infusion of dexamethasone or a membrane-impermeant dexamethasone-BSA conjugate into the PVN rapidly inhibits restraint-induced ACTH and corticosterone release in a manner consistent with feedback actions at the cell membrane. The dexamethasone fast feedback response is blocked by the cannabinoid CB1 receptor antagonist AM-251, suggesting that fast feedback requires local release of endocannabinoids. Hypothalamic tissue content of the endocannabinoid 2-arachidonoyl glycerol is elevated by restraint stress, consistent with endocannabinoid action on feedback processes. These data support the hypothesis that glucocorticoid-induced fast feedback inhibition of the HPA axis is mediated by a nongenomic signaling mechanism that involves endocannabinoid signaling at the level of the PVN.
糖皮质激素激素是对激活下丘脑-垂体-肾上腺皮质（HPA）轴的刺激做出反应而分泌的，并通过负反馈进行自我调节。人们认为快速时间尺度上发生的负反馈通过非基因组机制起作用。在这些研究中，我们通过直接在下丘脑室旁核（PVN）发挥糖皮质激素作用，研究了 HPA 轴应激反应的快速反馈抑制。将地塞米松或不能透过细胞膜的地塞米松-BSA 缀合物局部输注到 PVN 中，以与细胞膜反馈作用一致的方式快速抑制束缚诱导的 ACTH 和皮质酮释放。大麻素 CB1 受体拮抗剂 AM-251 阻断了地塞米松的快速反馈反应，表明快速反馈需要局部释放内源性大麻素。束缚应激会增加下丘脑组织中内源性大麻素 2-花生四烯酸甘油的含量，这与内源性大麻素对反馈过程的作用一致。这些数据支持这样的假设，即糖皮质激素诱导的 HPA 轴快速反馈抑制是由一种非基因组信号机制介导的，该机制涉及到 PVN 水平的内源性大麻素信号。
