Estrogen rapidly modulates 5-hydroxytrytophan-induced visceral hypersensitivity via GPR30 in rats. Gastroenterology [Gastroenterology] Journal article

BACKGROUND & AIMS:: Sex hormones have been reported to modulate visceral hypersensitivity (VH). Estrogen regulates neurons not only by binding to estrogen receptors (ER? and ER?) 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 17?- estradiol, progesterone, or both. ER ?/ss 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 ER/ss agonist, rapidly restored VH. VH was preserved by co-administration of ICI-182,780 and estrogen, but was absent after administration of the GPR30 antisense oligodeoxynucleotide. GPR30 co-localized 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.

Gastroenterology [Gastroenterology]