Hongqiao International Institute of Medical Research, Tongren Hospital and Department of Physiology, Faculty of Basic Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, China.
CNS Neurosci Ther. 2017 Dec;23(12):980-989. doi: 10.1111/cns.12769. Epub 2017 Oct 18.
Estrogens are known to exert a wide spectrum of actions on brain functions including modulation of pain. Besides the circulating estrogens produced mainly by the ovaries, many brain regions are also capable of de novo synthesizing estrogens, which may exert important modulatory effects on neuronal functions. This study was aimed to test the hypothesis that aromatase, the enzyme that catalyzes the conversion of testosterone to estradiols, may be distributed in the rostral ventromedial medulla (RVM), where it may impact on visceral pain.
Adult female rats were treated with cyclophosphamide (CPM, 50 mg/kg, ip, once every 3 days) or saline. At approximately day 10 following the 3rd injection, CPM-treated rats exhibited colorectal hyperalgesia as they showed significantly greater abdominal withdrawal responses (AWR) to graded colorectal distension (CRD, 0-100 mm Hg) than the saline group. Immunofluorescent staining and Western blot assay revealed that CPM-induced colorectal hyperalgesia was associated with significantly increased expression of aromatase and phosphorylated μ-type opioid receptor (pMOR) and decreased expression of total MOR in the RVM. Intracisternal application of aromatase inhibitors, fadrozole, and letrozole reversed CPM-induced colorectal hyperalgesia and restored pMOR and MOR expression in the RVM.
Our observations confirmed the expression of aromatase in the RVM, a pivotal brain region in descending modulation of pain and opioid analgesia. The results support the hypothesis that locally produced estrogens in the RVM may be involved in the maintenance of chronic visceral hyperalgesia and the downstream signaling may involve phosphorylation of MOR.
雌激素对大脑功能有广泛的作用，包括调节疼痛。除了主要由卵巢产生的循环雌激素外，许多大脑区域也能够从头合成雌激素，这可能对神经元功能产生重要的调节作用。本研究旨在检验芳香酶（一种催化睾酮转化为雌二醇的酶）可能分布在延髓头端腹内侧区（RVM），并可能影响内脏疼痛的假设。
成年雌性大鼠用环磷酰胺（CPM，50mg/kg，ip，每 3 天一次）或生理盐水处理。在第 3 次注射后大约 10 天，CPM 处理的大鼠表现出结直肠痛觉过敏，因为它们对分级结直肠扩张（CRD，0-100mmHg）的腹部退缩反应（AWR）明显大于生理盐水组。免疫荧光染色和 Western blot 分析显示，CPM 诱导的结直肠痛觉过敏与 RVM 中芳香酶和磷酸化 μ 型阿片受体（pMOR）表达显著增加以及总 MOR 表达减少有关。鞘内应用芳香酶抑制剂法舒地尔和来曲唑可逆转 CPM 诱导的结直肠痛觉过敏，并恢复 RVM 中的 pMOR 和 MOR 表达。
我们的观察结果证实了芳香酶在 RVM 中的表达，RVM 是下行调节疼痛和阿片类镇痛的关键脑区。结果支持局部产生的 RVM 中的雌激素可能参与维持慢性内脏痛觉过敏的假说，下游信号可能涉及 MOR 的磷酸化。
