Contribution of Sensory Neurons to Sex Difference in the Development of Stress-Induced Gastric Mucosal Injury in Mice

Background & Aims: 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 (PGI2). 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-PGF1α, a stable metabolite of PGI2, 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-PGF1α 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 μg/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.