Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
Cereb Cortex. 2013 Sep;23(9):2190-203. doi: 10.1093/cercor/bhs201. Epub 2012 Jul 10.
The rostral anterior cingulate cortex (rACC) is a key structure of pain affect. Whether and how estrogen in the rACC regulates pain-related negative emotion remains unclear. Behaviorally, using formalin-induced conditioned place aversion (F-CPA) in rats, which is believed to reflect the pain-related negative emotion, we found that estrogen receptor (ER) inhibitor ICI 182, 780 (ICI, 7α,17β-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol) or inhibitor of aromatase androstatrienedione into the rACC completely blocked F-CPA in either sex. An analogous effect was also observed in ovariectomy rats. Furthermore, exogenous estrogen in the absence of a formalin noxious stimulus was sufficient to elicit CPA (E-CPA) in both sexes by activating the membrane estrogen receptors (mERs) and N-methyl-D-aspartic acid (NMDA) receptors (NMDARs). Electrophysiologically, we demonstrated that estrogen acutely enhanced the glutamatergic excitatory postsynaptic currents (EPSCs) in rACC slices by increasing the ratio of NMDA-EPSCs to α-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid -EPSCs and presynaptic glutamate release. Interestingly, a brief exposure to estrogen elicited a persistent enhancement of NMDA-EPSCs, and this NMDA-long-term potentiation required the activation of the mERs, protein kinase A and NMDAR subunit NR2B. Finally, estrogen induced rapid dendritic spine formation in cultured rACC neurons. These results suggest that estrogen in the rACC, as a neuromodulator, drives affective pain via facilitating NMDA receptor-mediated synaptic transmission.
额前扣带皮质前部（rACC）是疼痛情感的关键结构。rACC 中的雌激素是否以及如何调节与疼痛相关的负面情绪尚不清楚。行为上，我们使用大鼠福尔马林诱导的条件性位置厌恶（F-CPA），这被认为反映了与疼痛相关的负面情绪，发现雌激素受体（ER）抑制剂 ICI 182,780（ICI，7α,17β-[9-（4,4,5,5,5-五氟戊基）亚磺酰基]壬基]雌-1,3,5(10)-三烯-3,17-二醇）或芳香酶抑制剂androstatrienedione 注入 rACC 完全阻断了无论性别如何的 F-CPA。类似的效果也在卵巢切除大鼠中观察到。此外，外源性雌激素在没有福尔马林有害刺激的情况下足以通过激活膜雌激素受体（mERs）和 N-甲基-D-天冬氨酸（NMDA）受体（NMDARs）在两性中引起 CPA（E-CPA）。电生理上，我们证明雌激素通过增加 NMDA-EPSC 与 α-氨基-3-（5-甲基-3-氧代-1,2-恶唑-4-基）丙氨酸-EPSC 的比值和突触前谷氨酸释放，急性增强 rACC 切片中的谷氨酸能兴奋性突触后电流（EPSCs）。有趣的是，短暂暴露于雌激素会引起 NMDA-EPSC 的持久增强，这种 NMDA 长时程增强需要 mERs、蛋白激酶 A 和 NMDAR 亚基 NR2B 的激活。最后，雌激素诱导培养的 rACC 神经元中快速的树突棘形成。这些结果表明，rACC 中的雌激素作为神经调质，通过促进 NMDA 受体介导的突触传递来驱动情感性疼痛。
