Ji Y, Bai G, Cao D-Y, Traub R J
Department of Neural and Pain Sciences, University of Maryland School of Dentistry, UM Center to Advance Chronic Pain Research, Baltimore, MD, USA.
Neurogastroenterol Motil. 2015 Jun;27(6):775-86. doi: 10.1111/nmo.12549. Epub 2015 Mar 24.
We previously reported estrogen modulates spinal N-methyl-d-aspartate (NMDA) receptor processing of colorectal pain through changes in spinal GluN1 subunit phosphorylation/expression. The purpose of this study was to investigate whether spinal GluN2B containing NMDA receptors are involved in estrogen modulation of visceral pain processing.
Behavioral, molecular, and immunocytochemical techniques were used to determine spinal GluN2B expression/phosphorylation and function 48 h following subcutaneous injection of estradiol (E2) or vehicle (safflower oil, Saff oil) in ovariectomized rats in the absence or presence of colonic inflammation induced by mustard oil.
E2 increased the magnitude of the visceromotor response (VMR) to colorectal distention compared to Saff oil in non-inflamed rats. Intrathecal injection of the GluN2B subunit antagonist, Ro 25-6981, had no effect on the VMR in non-inflamed E2 or Saff oil rats. Colonic inflammation induced visceral hyperalgesia in E2, but not Saff oil rats. Visceral hyperalgesia in E2 rats was blocked by intrathecal GluN2B subunit selective antagonists. In inflamed rats, E2 increased GluN2B protein and gene expression in the thoracolumbar (TL), but not lumbosacral (LS), dorsal spinal cord. Immunocytochemical labeling showed a significant increase in GluN2B subunit in the superficial dorsal horn of E2 rats compared to Saff oil rats.
CONCLUSIONS & INFERENCES: These data support the hypothesis that estrogen increases spinal processing of colonic inflammation-induced visceral hyperalgesia by increasing NMDA receptor activity. Specifically, an increase in the activity of GluN2B containing NMDA receptors in the TL spinal cord by estrogen underlies visceral hypersensitivity in the presence of colonic inflammation.
我们之前报道过雌激素通过改变脊髓中谷氨酸N1（GluN1）亚基的磷酸化/表达来调节脊髓对结肠疼痛的N-甲基-D-天冬氨酸（NMDA）受体加工过程。本研究的目的是调查含有NMDA受体的脊髓谷氨酸2B（GluN2B）是否参与雌激素对内脏痛觉加工的调节。
采用行为学、分子生物学和免疫细胞化学技术，在去卵巢大鼠皮下注射雌二醇（E2）或溶剂（红花油）48小时后，在有无芥子油诱导的结肠炎症的情况下，测定脊髓GluN2B的表达/磷酸化及功能。
与溶剂组相比，E2增加了未发炎大鼠对结肠扩张的内脏运动反应（VMR）幅度。鞘内注射GluN2B亚基拮抗剂Ro 25-6981对未发炎的E2或溶剂组大鼠的VMR无影响。结肠炎症在E2组大鼠中诱导了内脏痛觉过敏，但在溶剂组大鼠中未出现。E2组大鼠的内脏痛觉过敏被鞘内注射GluN2B亚基选择性拮抗剂所阻断。在发炎大鼠中，E2增加了胸腰段（TL）而非腰骶段（LS）背脊髓中GluN2B蛋白和基因的表达。免疫细胞化学标记显示，与溶剂组大鼠相比，E2组大鼠浅表背角的GluN2B亚基显著增加。
这些数据支持以下假设，即雌激素通过增加NMDA受体活性来增强脊髓对结肠炎症诱导的内脏痛觉过敏的加工。具体而言，雌激素使TL脊髓中含GluN2B的NMDA受体活性增加是结肠炎症存在时内脏超敏反应的基础。
