High Estrogen Level Modifies Postoperative Hyperalgesia via GPR30 and MMP-9 in Dorsal Root Ganglia Neurons
High Estrogen Level Modifies Postoperative Hyperalgesia via GPR30 and MMP-9 in Dorsal Root Ganglia Neurons
复制标题
高雌激素水平通过背根神经节神经元中的 GPR30 和 MMP-9 改变术后痛觉过敏
DOI：
10.1007/s11064-020-03032-z
复制
发表时间：
2020
影响因子：
4.4
通讯作者：
Xiaoping Gu
中科院分区：
文献类型：
--
作者：
Ming Jiang;Yue Liu;Hao Wu;Zhengliang Ma;Xiaoping Gu
性激素的循环是影响女性疼痛的因素之一，其机制尚未完全了解。G蛋白偶联雌激素受体30（GPR 30）是已知参与机械性痛觉过敏的雌激素受体。研究表明基质金属蛋白酶-9（MMP-9）是外周/中枢神经系统超敏反应和神经炎症的重要组成部分，两者均参与痛觉过敏。在这里，卵巢切除的大鼠用低剂量或高剂量的雌激素替代治疗，然后制作足底切口。随后，通过测定切开前后的缩爪机械阈值来评价机械性异常性疼痛。在大鼠切口，高雌激素水平诱导术后痛觉过敏和上调GPR 30和MMP-9在背根神经节（DRG）。MMP-9主要表达在共表达GPR 30的DRG神经元中，并导致IL-1β的激活。鞘内注射GPR 30激动剂G1后，雌性大鼠低雌激素和足底切口继续表现出显着的痛觉过敏，直到48小时后切口。鞘内注射GPR 30拮抗剂G15可明显减轻高雌激素水平大鼠足底切口术后的痛觉过敏。腹腔注射N-乙酰半胱氨酸（一种可防止MMP-9上半胱氨酸残基氧化的半胱氨酸来源）可通过抑制DRG中MMP-9和IL-1β的活化，显著缓解高雌激素诱导的术后痛觉过敏。这些结果表明，切口大鼠中的高雌激素水平引起DRG中GPR 30和MMP-9上调，随后激活IL-1β，导致诱导的术后痛觉过敏。
The cycling of sex hormones is one of the factors affecting pain in females, and the mechanisms are not fully understood. G-protein coupled estrogen receptor 30 (GPR30) is the estrogen receptor known to be involved in mechanical hyperalgesia. Studies have demonstrated that matrix metalloproteinase-9 (MMP-9) is a critical component in peripheral/central nervous system hypersensitivity and neuroinflammation, both of which participate in hyperalgesia. Here, ovariectomized rats were treated with low or high dose estrogen replacement, and then plantar incisions were made. Subsequently, mechanical allodynia was evaluated by determining the paw withdrawal mechanical threshold before and after the incision. In rats with incisions, high estrogen levels induced postoperative hyperalgesia and upregulation of GPR30 and MMP-9 in dorsal root ganglia (DRGs). MMP-9 was expressed primarily in DRG neurons co-expressing GPR30, and led to the activation of IL-1β. After intrathecal injection of the GPR30 agonist G1, female rats with low estrogen and plantar incisions continued to exhibit significant hyperalgesia until 48 h post-incision. In high estrogen level rats with plantar incisions, intrathecal injection of GPR30 antagonist G15 significantly attenuated postoperative hyperalgesia. Intraperitoneal injection of N-acetyl-cysteine, a source of cysteine that prevents the oxidation of cysteine residues on MMP-9, significantly relieved high estrogen-induced postoperative hyperalgesia via suppression of MMP-9 and IL-1β activation in DRGs. These results demonstrate that high estrogen level in rats with incisions elicit GPR30 and MMP-9 upregulation in DRGs and subsequently activate IL-1β, leading to induced postoperative hyperalgesia.