title: Estrogen facilitates spinal cord synaptic transmission via membrane-bound estrogen receptors: implications for pain hypersensitivity.
abstract: Recent evidence suggests that estrogen is synthesized in the spinal dorsal horn and plays a role in nociceptive processes. However, the cellular and molecular mechanisms underlying these effects remain unclear. Using electrophysiological, biochemical, and morphological techniques, we here demonstrate that 17β-estradiol (E2), a major form of estrogen, can directly modulate spinal cord synaptic transmission by 1) enhancing NMDA receptor-mediated synaptic transmission in dorsal horn neurons, 2) increasing glutamate release from primary afferent terminals, 3) increasing dendritic spine density in cultured spinal cord dorsal horn neurons, and 4) potentiating spinal cord long term potentiation (LTP) evoked by high frequency stimulation (HFS) of Lissauer's tract. Notably, E2-BSA, a ligand that acts only on membrane estrogen receptors, can mimic E2-induced facilitation of HFS-LTP, suggesting a nongenomic action of this neurosteroid. Consistently, cell surface biotinylation demonstrated that three types of ERs (ERα, ERβ, and GPER1) are localized on the plasma membrane of dorsal horn neurons. Furthermore, the ERα and ERβ antagonist ICI 182,780 completely abrogates the E2-induced facilitation of LTP. ERβ (but not ERα) activation can recapitulate E2-induced persistent increases in synaptic transmission (NMDA-dependent) and dendritic spine density, indicating a critical role of ERβ in spinal synaptic plasticity. E2 also increases the phosphorylation of ERK, PKA, and NR2B, and spinal HFS-LTP is prevented by blockade of PKA, ERK, or NR2B activation. Finally, HFS increases E2 release in spinal cord slices, which can be prevented by aromatase inhibitor androstatrienedione, suggesting activity-dependent local synthesis and release of endogenous E2.
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Xiao-Meng
authors.initials: XM
authors.lastname: Zhang
authors.forename: Zhi-Qi
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: Yu-Qiu
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D019921:Biotinylation; D004594:Electrophysiology / Q000379:methods; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism; D059225:Nociception; D010146:Pain / Q000188:drug therapy*; D010766:Phosphorylation; D020671:Posterior Horn Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D016202:N-Methylaspartate