Estrogen Facilitates Spinal Cord Synaptic Transmission via Membrane-bound Estrogen Receptors

Zhang, Yan; Xiao, Xiao; Zhang, Xiaomeng; Zhao, Zhi‐Qi; Zhang, Yu‐Qiu

doi:10.1074/jbc.m112.368142

Cited by 47 publications

(35 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3, lane B). The molecular mass of this signal is comparable to that previously reported for rat spinal GPR30, also assessed via Western blotting [51]. While the observed co-immunoprecipitation does not unequivocally indicate a direct physical association between ERα and GPR30, it does indicate that they coexist within a common complex.…”

Section: Resultssupporting

confidence: 80%

Estrogens Suppress Spinal Endomorphin 2 Release in Female Rats in Phase with the Estrous Cycle

Kumar¹,

Storman²,

Liu³

et al. 2015

Neuroendocrinology

View full text Add to dashboard Cite

Background/Aims: Male and female rats differ in their ability to utilize spinal endomorphin 2 (EM2; the predominant mu-opioid receptor ligand in spinal cord) and in the mechanisms that underlie spinal EM2 analgesic responsiveness. We investigated the relevance of spinal estrogen receptors (ERs) to the in vivo regulation of spinal EM2 release. Methods: ER antagonists were administered directly to the lumbosacral spinal cord of male and female rats, intrathecal perfusate was collected, and resulting changes in EM2 release were quantified using a plate-based radioimmunoassay. Results: Intrathecal application of an antagonist of either estrogen receptor-α (ERα) or the ER GPR30 failed to alter spinal EM2 release. Strikingly, however, the concomitant blockade of ERα and GPR30 enhanced spinal EM2 release. This effect was sexually dimorphic, being absent in males. Furthermore, the magnitude of the enhancement of spinal EM2 release in females was dependent upon estrous cycle stage, suggesting a relationship with circulating levels of 17β-estradiol. The rapid onset of enhanced EM2 release following intrathecal application of ERα/GPR30 antagonists (within 30-40 min) suggests mediation via ERs in the plasma membrane, not the nucleus. Notably, both ovarian and spinally synthesized estrogens are essential for membrane ER regulation of spinal EM2 release. Conclusion: These findings underscore the importance of estrogens for the regulation of spinal EM2 activity and, by extension, endogenous spinal EM2 antinociception in females. Components of the spinal estrogenic mechanism(s) that suppress EM2 release could represent novel drug targets for improving utilization of endogenous spinal EM2, and thereby pain management in women.

show abstract

Section: Resultssupporting

confidence: 80%

Estrogens Suppress Spinal Endomorphin 2 Release in Female Rats in Phase with the Estrous Cycle

Kumar¹,

Storman²,

Liu³

et al. 2015

Neuroendocrinology

View full text Add to dashboard Cite

show abstract

“…A downstream activation of ERK is suggested since ERK inhibition prevented PKC- and PKA-mediated modulation of A-type K + current (Hu and Gereau, 2003) as well as action potentials in the superficial dorsal horn neurons (Hu et al, 2003). A recent study has also reported estradiol-induced phosphorylation of spinal PKA and ERK (Zhang et al, 2012). In addition, Gs coupling of membrane ERα and GPR30 is expected to induce adenylyl cyclase-mediated activation of cAMP-dependent PKA (Razandi et al, 1999; Filardo et al, 2007).…”

Section: Discussionmentioning

confidence: 95%

“…All estrogen receptors (ERα, β, GPR30 and Gq-mER) are shown to be localized in spinal dorsal horn neurons (Shughrue et al, 1997; Papka et al, 2001; Dun et al, 2009; Zhang et al, 2012). Gq-mER, as the name suggests, is coupled to Gα q protein that induces cellular cascades (Qiu et al, 2003; Figure 7) beginning by activation of phospholipase C β (PLCβ), DAG-induced activation of PKCδ and in turn, PKA which may phosphorylate, and thus inhibit potassium channel (including GIRK) function.…”

Section: Discussionmentioning

confidence: 99%

“…Molarities used are of E2 in E2BSA. The highest dose of E2BSA (0.5 mM) is in fact a commonly used dose of estradiol and was derived from previously reported intrathecally applied estradiol that enhanced baroreflex function and autonomic tone and evoked action potentials in spinal neurons (Saleh et al,2000; Zhang et al, 2012). All four estrogen receptor subtype selective agonists used in this study have several fold higher potency towards their target receptor subtype as compared to other estrogen receptor subtypes.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Activation of a Gq-coupled membrane estrogen receptor rapidly attenuates α2-adrenoceptor-induced antinociception via an ERK I/II-dependent, non-genomic mechanism in the female rat

Nag

Mokha

2014

Neuroscience

View full text Add to dashboard Cite

Though sex differences in pain and analgesia are known, underlying mechanisms remain elusive. This study addresses the selective contribution of membrane estrogen receptors (mER) and mER-initiated non-genomic signaling mechanisms in our previously reported estrogen-induced attenuation of α2- adrenoceptor-mediated antinociception. By selectively targeting spinal mERs in ovariectomized female rats using E2BSA (membrane impermeant estradiol analogue), and ERα selective agonist PPT, ERβ selective agonist DPN, GPR 30 agonist G1 and Gq-coupled mER (Gq-mER) agonist STX, we provide strong evidence that Gq-mER activation may solely contribute to suppressing clonidine (an α2- adrenoceptor agonist)-induced antinociception, using the nociceptive tail flick test. Increased tail flick latencies (TFL) by intrathecal (i.t.) clonidine were not significantly altered by i.t. PPT, DPN, or G1. In contrast, E2BSA or STX rapidly and dose-dependently attenuated clonidine-induced increase in TFL. ICI 182,780, the ER antagonist, blocked this effect. Consistent with findings with the lack of effect of ERα and ERβ agonists that modulate receptor-regulated transcription, inhibition of de novo protein synthesis using anisomycin also failed to alter the effect of E2BSA or STX, arguing against a contribution of genomic mechanisms. Immunoblotting of spinal tissue revealed that mER activation increased levels of phosphorylated extracellular signal regulated kinase (ERK) but not of protein kinase A (PKA) or C (PKC). In vivo inhibition of ERK with U0126 blocked the effect of STX and restored clonidine antinociception. Although estrogen-induced delayed genomic mechanisms may still exist, data presented here indicate that Gq-mER may solely mediate estradiol-induced attenuation of clonidine antinociception via a rapid, reversible, and ERK-dependent, non-genomic mechanism, suggesting that Gq-mER blockade might provide improved analgesia in females.

show abstract

“…With continued ovulation induction, follicular recruitment results in significant bilateral ovarian enlargement from multiple follicles and supraphysiologic estradiol levels. In recent years, estradiol (E2) has been increasingly studied as a modulator of pain involved at the level of the dorsal horn and NMDA transmission [6][7][8]. However, the impact on pain modulation and pain perception of the supraphysiologic levels of estradiol and the overall altered endocrine state seen in ART, have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Hormonal and Clinical Predictors for Post–egg Retrieval Pain in Women Undergoing Assisted Reproductive Technology Procedures

Vuilleumier

Dinges

Ciliberto

et al. 2016

The Clinical Journal of Pain

View full text Add to dashboard Cite

ObjectivesThe intensity of post-egg retrieval pain is underestimated, with few studies examining postprocedural pain and predictors to identify women at risk for severe pain. We evaluated the influence of pre-procedural hormonal levels, ovarian factors, as well as mechanical temporal summation (mTS) as predictors for post-egg retrieval pain in women undergoing in vitro fertilization (IVF). MethodsEighteen women scheduled for ultrasound-guided egg retrieval under standardized anesthesia and post-procedural analgesia were enrolled. Pre-procedural mTS, questionnaires, clinical data related to anesthesia and the procedure itself, post-procedural pain scores and pain medication for breakthrough pain were recorded. Statistical analysis included Pearson product moment correlations, Mann-Whitney U tests and multiple linear regressions. ResultsAverage peak post-egg retrieval pain during the first 24 hours was 5.0 ± 1.6 on an NRS scale (0=no pain, 10=worst pain imaginable). Peak post-egg retrieval pain was correlated with basal antimullerian hormone (AMH) (r=0.549, p=0.018), pre-procedural peak estradiol (r=0.582, p=0.011), total number of follicles (r=0.517, p=0.028) and number of retrieved eggs (r=0.510, p=0.031). Ovarian hyperstimulation syndrome (OHSS) (n=4) was associated with higher basal AMH (p=0.004), higher peak pain scores (p=0.049), but not with peak estradiol (p=0.13). The mTS did not correlate with peak post-procedural pain (r=0.266, p=0.286), or peak estradiol level (r=0.090, p=0.899).Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited. DiscussionPeak post-egg retrieval pain intensity was higher than anticipated. Our results suggest that post-egg retrieval pain can be predicted by baseline AMH, high peak estradiol, and OHSS.Further studies to evaluate intra-and post-procedural pain in this population are needed, as well as clinical trials to assess post-procedural analgesia in women presenting with high hormonal levels.

show abstract

Estrogen Facilitates Spinal Cord Synaptic Transmission via Membrane-bound Estrogen Receptors

Cited by 47 publications

References 66 publications

Estrogens Suppress Spinal Endomorphin 2 Release in Female Rats in Phase with the Estrous Cycle

Estrogens Suppress Spinal Endomorphin 2 Release in Female Rats in Phase with the Estrous Cycle

Activation of a Gq-coupled membrane estrogen receptor rapidly attenuates α2-adrenoceptor-induced antinociception via an ERK I/II-dependent, non-genomic mechanism in the female rat

Hormonal and Clinical Predictors for Post–egg Retrieval Pain in Women Undergoing Assisted Reproductive Technology Procedures

Contact Info

Product

Resources

About