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Estrogen rapidly modulates 5-hydroxytrytophan-induced visceral hypersensitivity via GPR30 in rats.

Abstract：

BACKGROUND & AIMS:Sex hormones have been reported to modulate visceral hypersensitivity (VH). Estrogen regulates neurons not only by binding to estrogen receptors (ERalpha and ERbeta) to initiate transcription but also via the G-protein coupled receptor GPR30, which binds and rapidly mediates actions of estrogen. We examined the role of sex hormones in a VH model without colonic inflammation. METHODS:5-Hydroxytryptophan (5HTP) was injected subcutaneously into awake female rats to induce VH; the 5HT3 antagonist (granisetron) or saline (control) were injected 30 minutes later. Immunohistochemistry was used to quantify calcitonin gene-related peptide-immunoreactive (CGRP-IR) neurons in the dorsal root ganglion (DRG). 5HTP-induced VH was evaluated in ovariectomized rats injected with 17beta-estradiol, progesterone, or both. ER alpha/beta agonist, GPR30 agonist, ER antagonist (ICI-182,780) or GPR30 antisense oligodeoxynucleotide were given to 5HTP-primed, estrogen-treated ovariectomized rats. RESULTS:Rats given 5HTP had increased VH that was inhibited by granisetron, accompanied by a decrease in CGRP-IR in the DRG. Ovariectomy eliminated 5HTP-induced VH, whereas estrogen and the combination of estrogen and progesterone, but not progesterone alone, restored the VH. The GPR30 agonist, but not the ERbeta agonist, rapidly restored VH. VH was preserved by coadministration of ICI-182,780 and estrogen but was absent after administration of the GPR30 antisense oligodeoxynucleotide. GPR30 colocalized with 5HT3 in DRG neurons; no significant inflammation occurred in colonic mucosa. CONCLUSIONS:In the absence of mucosal inflammation, estrogen can rapidly modulate 5HTP-induced VH. Loss of gonad hormones suppresses VH, whereas estrogen replacement restores it. Estrogen-mediated VH appears to act through GPR30.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Lu CL,Hsieh JC,Dun NJ,Oprea TI,Wang PS,Luo JC,Lin HC,Chang FY,Lee SD

doi

10.1053/j.gastro.2009.03.047

subject

Has Abstract

pub_date

2009-09-01 00:00:00

pages

1040-50

issue

3

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(09)00508-3

journal_volume

137

pub_type

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