Estrogen in the anterior cingulate cortex contributes to pain-related aversion.
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.
Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
Xiao
X
Xiao
Yan
Y
Yang
Yan
Y
Zhang
Xiao-Meng
XM
Zhang
Zhi-Qi
ZQ
Zhao
Yu-Qiu
YQ
Zhang
D000339:Affect / Q000502:physiology*; D000818:Animals; D003213:Conditioning, Psychological / Q000502:physiology; D004958:Estradiol / Q000502:physiology*; D005260:Female; D006179:Gyrus Cinguli / Q000503:physiopathology*; D008297:Male; D009473:Neuronal Plasticity; D010052:Ovariectomy; D010146:Pain / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D009435:Synaptic Transmission
D011960:Receptors, Estrogen; D016194:Receptors, N-Methyl-D-Aspartate; D004958:Estradiol