Contribution of sensory neurons to sex difference in the development of stress-induced gastric mucosal injury in mice.
OBJECTIVE
Sensory neurons play a critical role in reducing stress-induced gastric mucosal injury by releasing calcitonin gene-related peptide (CGRP) through an increase in gastric mucosal levels of prostacyclin (PGI(2)). Because estrogen enhances nerve growth factor-mediated CGRP production in sensory neurons, we hypothesized that stress-induced gastric mucosal injury occurs less in females than in males.


METHODS
Gastric ulcer index, gastric myeloperoxidase activity, and gastric tissue levels of CGRP and 6-keto-PGF(1alpha), a stable metabolite of PGI(2), were determined in male and female wild-type (CGRP(+/+)) mice and CGRP knockout (CGRP(-/-)) mice subjected to water-immersion restraint stress.


RESULTS
In CGRP(+/+) mice, ulcer index and myeloperoxidase activities were lower and gastric tissue levels of CGRP and 6-keto-PGF(1alpha) were higher in female mice than in male mice, but there were no such sex differences in CGRP(-/-)mice. Sex differences in CGRP(+/+) mice were eliminated by pretreatment with SB366791 (500 microg/kg intraperitoneally), a vanilloid receptor antagonist, and by ovariectomy. Reversal of sex differences by ovariectomy was not observed in female CGRP(+/+) mice with estradiol replacement (1 mg . kg(-1). wk(-1) for 3 weeks). Levels of CGRP messenger RNA in dorsal root ganglion neurons isolated from female CGRP(+/+) mice were decreased by ovariectomy, and these decreases were reversed by estradiol replacement.


CONCLUSIONS
Estrogen-mediated increases in CGRP levels in sensory neurons might contribute to reduce stress-induced gastric mucosal injury by attenuating inflammatory responses. This might at least partly explain the sex difference observed in the development of stress-induced gastric mucosal injury in mice.
Shimozawa
Nobuhiko
N
Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan.
Okajima
Kenji
K
Harada
Naoaki
N
Arai
Masatoku
M
Ishida
Yusuke
Y
Shimada
Shoichi
S
Kurihara
Hiroki
H
Nakagata
Naomi
N
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D002934:Cinnamates / Q000494:pharmacology; D011464:Epoprostenol / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007101:Immersion / Q000009:adverse effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000378:metabolism*; D010052:Ovariectomy; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D011460:Prostaglandins F / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D013276:Stomach Ulcer / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013312:Stress, Physiological / Q000209:etiology / Q000378:metabolism*
D000813:Anilides; D002934:Cinnamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D011460:Prostaglandins F; D012333:RNA, Messenger; D004958:Estradiol; D011464:Epoprostenol; D009195:Peroxidase; D015740:Calcitonin Gene-Related Peptide; C100006:prostaglandin F1