Estrogen Rapidly Modulates 5-Hydroxytrytophan-Induced Visceral Hypersensitivity via GPR30 in Rats

Lu, Ching–Liang; Hsieh, Jen-Chuen; Dun, Nae J.; Oprea, Tudor I.; Wang, Paulus S.; Luo, Jiing‐Chyuan; Lin, Han‐Chieh; Chang, Full‐Young; Lee, Shou–Dong

doi:10.1053/j.gastro.2009.03.047

Cited by 48 publications

(42 citation statements)

References 40 publications

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“…Indeed, in both rodent and human females pain threshold and pain tolerance vary in relationship to the stage of the estrous cycle with increased mechanosensation, presumably acting by way of low-threshold myelinated afferents, being implicated as a potential underlying mechanism. (56) These data are consistent with recent observations that GPR30 ER agonists can induce mechanical hyperalgesia and visceral hypersensitivity in the rat (27,34). Collectively, these reports are consistent with our previous demonstration (30) that lowthreshold myelinated Ah-type VGN can be sensitized through agonist activation of purinergic (P 2x ) receptors that have long been associated with afferent signaling of pain and inflammatory responses (51).…”

Section: Discussionsupporting

confidence: 82%

17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

Qiao

et al. 2009

American Journal of Physiology-Cell Physiology

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Qiao GF, Li BY, Lu YJ, Fu YL, Schild JH. 17␤-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats. Am J Physiol Cell Physiol 297: C654 -C664, 2009. First published July 1, 2009 doi:10.1152/ajpcell.00059.2009.-We recently identified a myelinated vagal afferent subpopulation (Ah type) far more prevalent in female than male rats and showed that this difference extends to functionally specific visceral sensory afferents, baroreceptors of the aortic arch. Excitability of myelinated Ah-type afferents is markedly reduced after ovariectomy (OVX). Here we tested the hypothesis that 17␤-estradiol can selectively restore excitability of these sex-specific vagal afferents. Acutely isolated vagal afferent neurons (VGN) from intact and OVX adult female rats were used with patch-clamp technique and current-clamp protocols to assess the effect of acute application of 17␤-estradiol on neuronal excitability. At over physiologically relevant 17␤-estradiol concentrations for rat (1-10 nM) excitability of myelinated Ah-type vagal afferents is restored to discharge frequencies comparable to those in intact females, albeit with some interesting differences related to burst and sustained patterns of neuronal discharge. Restoration of excitability occurs within 3 min of hormone application and is stereo specific, because 1,000 nM 17␣-estradiol fails to alter excitability. Furthermore, activation of G protein-coupled estrogen receptor GPR30 with highly selective agonist G-1 similarly restores excitability of Ah-type afferents. The effectiveness of 17␤-estradiol and G-1 is completely eliminated by application of high-affinity estrogen receptor ligand ICI-182,780. 17␤-Estradiol conjugated with BSA is ϳ70% as effective as 17␤-estradiol alone in restoring Ah-type VGN excitability. These data support our conclusions that the cellular mechanisms leading to rapid restoration of neuronal excitability of myelinated Ah-type VGN after OVX occur, at least in part, via membrane-bound estrogen receptors. We contend that recovery of high-frequency discharge at physiologically relevant 17␤-estradiol concentrations implies that this unique subtype of low-threshold myelinated vagal afferent may account for some of the sex-related differences in visceral organ system function. Sex differences in cardiovascular and gastrointestinal function and the potential role of GPR30 in modulation of sex-specific myelinated Ah-type vagal afferents are discussed. sensory afferent; visceral afferent; estrogen receptor; GPR30; ovariectomy VISCERAL AFFERENTS with cell bodies in the vagal ganglia innervate a functionally diverse range of organs associated with the cardiovascular, gastrointestinal, and pulmonary systems. Vagal afferent mediation of the reflexogenic properties of the autonomic nervous system (ANS) in addition to visceral sensation is well recognized (for review see Ref. 55). Because the peripheral sensory terminals can be influenced by a wide range of endogenous chemicals released as a consequenc...

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Section: Discussionsupporting

confidence: 82%

17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

Qiao

et al. 2009

American Journal of Physiology-Cell Physiology

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“…Furthermore, a study conducted by Gao et al showed opposing effects of GPR30 and classical estradiol signaling on cell proliferation in the mouse uterine tissue involving modulation of ERK phosphorylation [25]. Finally, Lu et al observed that estrogen-mediated visceral hypersensitivity is GPR30-dependent in models without colonic inflammation [26]. To sum up, the complex relationship between ERs and GPR30 and its role in the inflammatory process in the gut, along with quantification of estradiol levels in IBD patients requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…The idiopathic J Gastrointestin Liver Dis, March 2017 Vol. 26 No 1: [29][30][31][32][33][34][35] inflammatory intestinal process related to IBD is strongly associated with a decreased patient's quality of life and requires advanced clinical intervention. However, a significant rate of loss of response or even the lack of any therapeutic effect is often observed with currently available anti-IBD treatments.…”

Section: Introductionmentioning

confidence: 99%

G Protein-Coupled Receptor 30 (GPR30) Expression Pattern in Inflammatory Bowel Disease Patients Suggests its Key Role in the Inflammatory Process. A Preliminary Study

Włodarczyk

Sobolewska-Włodarczyk

Cygankiewicz

et al. 2020

JGLD

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Background & Aims: G protein-coupled receptor 30 (GPR30) is a recently de-orphanized estrogen receptor that mediates the effects of estrogens on different cells. It has been postulated that in inflammatory bowel diseases (IBD) activation of GPR30 blocks the pathways dependent on pro-inflammatory cytokines. The aim of our study was to investigate GPR30 expression in patients with IBD and its potential implication in future therapies.Methods. Fifty-seven patients were enrolled in our study: 20 subjects with Crohn’s disease (CD), 22 with ulcerative colitis (UC) and 15 controls. In each subject, biopsies were taken from various left-colonic locations. Gene and protein expression of GPR30 was quantified using real time RT-PCR or Western blot.Results: GPR30 mRNA and protein expression were detected in all tested colonic tissues. No significant differences in GPR30 gene expression were observed. In non-inflamed areas, GPR30 protein was strongly increased in CD patients, but moderately in UC patients (p= 0.014 and p=0.143, respectively, vs. controls). In CD patients, a significantly lower GPR30 protein content in inflamed than in non-inflamed tissue was observed (p=0.039). The change was independent of patient gender.Conclusion: Our observations indicate that GPR30 may play a role in the development and progression of inflammatory lesions in IBD, thus affecting disease severity, and consequently IBD treatment. Therefore, GPR30 may become an attractive target for novel anti-IBD drugs, particularly in CD.Abbreviations: CRP: C-reactive protein; C-IBS: constipation-predominant IBS; CD: Crohn’s disease; D-IBS: diarrhea-predominant IBS; ER: Estrogen; GPER: G protein – coupled estrogen receptor 1; GPR30: G protein-coupled receptor 30; GI: gastrointestinal; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; IBD: inflammatory bowel diseases; IL: Interleukin; ICAM-1: intracellular cell adhesion molecule-1; IBS: irritable bowel syndrome; PDL: periodontal ligament; Th: T helper; TNF-α: tumor necrosis factor-α; UC: ulcerative colitis; VCAM-1: vascular cell adhesion molecule-1; WBC: white blood cells.

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“…Estrogen regulates neurons not only by binding to estrogen receptors (ER␣ and ER␤) to initiate transcription but also by interacting with GPR30, which binds and rapidly mediates estrogen activities (Lu et al, 2009). Estrogen also influences the hypothalamic-pituitary-adrenal axis by interacting with corticosteroid receptors and corticotropinreleasing factor; these substances increase pain sensitivity (Myers and Greenwood-Van Meerveld, 2007;Myers et al, 2011).…”

Section: Estrogen Gpr30 and Chronic Painmentioning

confidence: 99%

Activation of GPR30 attenuates chronic pain-related anxiety in ovariectomized mice

Liu

Tian

Guo

et al. 2015

Psychoneuroendocrinology

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Estrogen Rapidly Modulates 5-Hydroxytrytophan-Induced Visceral Hypersensitivity via GPR30 in Rats

Cited by 48 publications

References 40 publications

17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

17β-Estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats

G Protein-Coupled Receptor 30 (GPR30) Expression Pattern in Inflammatory Bowel Disease Patients Suggests its Key Role in the Inflammatory Process. A Preliminary Study

Activation of GPR30 attenuates chronic pain-related anxiety in ovariectomized mice

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