Gastric Mucosal Injury In Rats Research Articles

Effect of melatonin on burn-induced gastric mucosal injury in rats

We studied the effect of melatonin treatment on gastric mucosal damage induced by experimental burns and its possible relation to changes in gastric lipid peroxidation status. Melatonin was intraperitoneally applied immediately after third-degree burns over 30% of total body skin surface area of rats. Malondialdehyde (MDA), uric acid (UA) and sulphydril (SH) levels were determined in gastric mucosa and blood plasma and used as biomarkers of the oxidative stress. The results showed that the skin burn caused oxidative stress evidenced by accumulation of MDA and UA as well as the depletion of SHs in gastric mucosa. Plasma MDA concentrations were elevated, while plasma SH concentrations were decreased after burns. Melatonin (10 mg per kg body weight) protected gastric mucosa from oxidative damage by suppressing lipid peroxidation and activating the antioxidant defence. It may be hypothesised that melatonin restores the redox balance in the gastric mucosa and protects it from burn-induced oxidative injury. Melatonin has no significant influence on the concentrations of plasma MDA and antioxidants after burn; therefore, it should largely be considered as a limiting factor for tissue-damage.

W1546 Contribution of Heat Shock Proteins Expression to Gender Difference in Development of Stress-Induced Gastric Mucosal Injury in Rats

Copyright © 200? JCBN Summary Recent studies have indicated that heat shock proteins (HSPs), which function as molecular chaperones, play important roles in cellular responses to stress-related events. However, the gender difference in the expression of HSP in the gastric mucosa remains unclear. In order to understand the mechanism of gender difference in the prevalence or severity of gastric mucosal lesions, the expression level of HSP and the correlation of estrogen to HSP induction in the gastric mucosa were evaluated in this study. The basal expression levels of HSP60 and HSP90 in the gastric mucosa were significantly higher in females than those in males. The gastric ulcer index was significantly higher in male rats compared to female rats observed after 12 h water immersion stress exposure. At this time point, the expression levels of HSP60 and HSP90 in the gastric mucosa were significantly higher in females than those in males. An estrogen-treatment significantly induced the expression of HSP60, HSP70 and HSP90 in the gastric mucosa. Inversely, an ovariectomy dramatically reduced the expression of HSP60, HSP70 and HSP90 in the gastric mucosa. Our results suggested that estrogen might play an important role in gastric mucosal protection with the induction of gastric mucosal HSPs.

Protective effects of DIDS against ethanol-induced gastric mucosal injury in rats

The compound 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) is an efficient anion exchanger inhibitor that can block the activities of anion exchanger 2 (AE2), which plays an indispensable role in gastric acid secretion. DIDS also has potent anti-oxidative and antiapoptosis activities. This study aimed to investigate the effect of DIDS on ethanol-induced mucosal damage in rats and to evaluate the underlying mechanisms that mediate the action of the compound. The rats received 1 ml of absolute ethanol or saline orally. DIDS [50 mg/kg intravenous (i.v.)] was given 5 min before ethanol administration. Gastric lesions were evaluated macroscopically, microscopically, and electron microscopically at 60 min after ethanol challenge. Gastric myeloperoxidase (MPO) activity, malonyldialdehyde (MDA) level, prostaglandin E2 (PGE2) synthesis, and cyclooxygenase-2 (COX-2) expression were assessed. For the evaluation of the effect of DIDS on gastric acid secretion, histamine-stimulatory gastric acid secretion was examined with or without pretreatment of DIDS (50 mg/kg; i.v.). Ethanol-induced gastric lesions were characterized by increasing gastric MDA level, MPO activity, and COX-2 expression, and decreasing PGE2 synthesis. It was found that DIDS significantly reduced the extent of gastric mucosal damage and reversed tissue MDA level and MPO activity. DIDS further enhanced the expression of COX-2 and reversed the decrease of PGE2. Our results suggested that DIDS is beneficial in rat model of gastric injury through mechanisms that involve inhibiting inflammatory cell infiltration and lipid peroxidation and up-regulating the COX-2/PGE2 pathway.

Effect of Sesame Oil on Acidified Ethanol‐Induced Gastric Mucosal Injury in Rats

Exposure of gastric mucosa to concentrated ethanol induces acute gastritis. Gastric mucosal lipid peroxidation plays a significant role in the pathogenesis of ethanol-induced gastric mucosal lesions. The aim of this study was to investigate the effect of sesame oil on acidified ethanol-induced gastric mucosal damage in rats. We performed gastric bilateral vagotomy in rats. A small incision on forestomach was made and stomach content was expelled. Normal artificial gastric acid (54 mM NaCl plus 100 mM HCl) or acidified ethanol (30% ethanol plus 150 mM HCl) was instilled into the stomach. Gastric lipid peroxidation, glutathione, and nitric oxide levels were measured 3 hours after acidified ethanol administration. Acidified ethanol caused mucosal ulceration, luminal hemorrhage, lipid peroxidation, and a lower level of mucosal glutathione and nitric oxide production. Pretreatment of sesame oil, but not mineral oil, significantly decreased acidified ethanol-induced mucosal ulcer formation and luminal hemorrhage. Sesame oil reduced mucosal lipid peroxidation, as well as glutathione and nitric oxide production in acidified ethanol-treated stomachs. Furthermore, both sesame oil and mineral oil did not affect serum ethanol concentration in acidified ethanol-treated rats. Sesame oil attenuates acidified ethanol-induced gastric mucosal injury by reducing oxidative stress in rats.

English

The present study was performed to evaluate the anti-ulcerogenic activity of hyaluronic acid against ethanol induced gastric mucosal injury in rats. Four groups of adultSprague Dawley rats were orally pre-treated respectively with distilled water (ulcer control groups), omeprazole (reference group), high molecular weight hyaluronic acid and 0.8% hyaluronic acid gel (experimental groups) one hour before oral administration of absolute ethanol to generate gastric mucosal. After an additional hour, the rats were sacrificed and the ulcer areas of the gastric walls were determined. Grossly, the ulcer control group exhibited severe mucosal injury, whereas pre-treatment with omeprazol, and both types of hyaluronic acid gel, exhibited significant protection of gastric mucosal injury. Histological studies of the gastric wall revealed that ulcer control group exhibited severe damage of gastric mucosa; along with edema and leucocytes infiltration of submucosal layer compared to rats pre-treated with hyaluronic acid gels which showed comparatively gastric mucosal protection, reduction or absence of edema and leucocytes infiltration of submucosal layer. The present finding suggests that high molecular weight hyaluronic acid gel promotes higher ulcer protection. Key words: Hyaluronic acid gel, cytoprotection, gastric ulcer, histology.

Protective effects of pentoxifylline on gastric mucosal injury in rats with endotoxemia

Objective To investigate the protective effects of pentoxifylline on gastric mucosal injury in rats with endotoxemia. Methods 30 Wistar rats were randomly divided into 3 groups : sham operated control group (C group) ,LPS group and PTX group. The serum tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) levels in each group were measured. The immunohistochemistry was used to assess the expression of the ICAM-1 in the gastric mucosal tissues. Results The levels of TNF-α and IL-1β in serum in LPS group were higher than those in C group (P <0.01). The level of ICAM-1 in the gastric mucosal tissues in LPS group was higher than those in sham operated control group(P < 0.01). After FIX treatment, the levels of TNF-α and IL-1β in serum in PTX group were lower than those in LPS group(P < 0.01) and the level of ICAM-1 in the hepatic tissues in PTX group was also lower than those in LPS group(P <0.01). Conclusions TNF-α,IL-1β and ICAM-1 take part in the progress of gastric mucosal inju-ry in rats with endotoxemia. PTX can eliminate the gastric mueesa injury and protect the gastric mucosal tissues by downregulating the levels of TNF-α, IL-1β and ICAM-1. Key words: Pentoxifylline; Endotoxemia; Gastric mucosa; injury; Intercellular adhesion molecule-1

Role of Rosiglitazone as a Gastroprotective Agent Against Indomethacin-Induced Gastric Mucosal Injury in Rats.

BackgroundRosiglitazone, an insulin sensitizing agent, has been recently implicated in the control of inflammatory processes and modulation of expression of various cytokines such as tumor necrosis factor (TNF-α). However, its mechanistic effect of gastric mucosal integrity remains to be elucidated.MethodsThe present study was designed to determine effect of rosiglitazone on gastric mucosal lesions induced by indomethacin (IND) in rats. Pyloric ligation was performed for the collection of gastric juice, and gastric ulceration was induced by a single intraperitoneal injection of IND (30 mg/kg).ResultsIND administration caused a significant decrease in the volume of gastric juice mucin and gastric mucosal nitrite and prostaglandin E2 (PGE2) levels. This was accompanied by a significant increase in gastric juice free and total acidity and pepsin activity. In addition, an elevation in the gastric mucosal lipid peroxide and serum TNF-α level was observed. Pretreatment with rosiglitazone (10 mg/kg, orally, for 1 weeks) resulted in a significant reduction in the elevated gastric mucosal lesions and lipid peroxides levels. This was associated with a marked increase in gastric juice mucin and a reduction in TNF-α level. Moreover, rosiglitazone significantly increased the gastric mucosal total nitrite and PGE2 levels.ConclusionsRosiglitazone exerts a gastroprotective effect against IND-induced gastric mucosal lesions and its anti-ulcer effect is mediated via scavenging free radicals, increasing NO, PGE2 and mucus production in addition to its anti-inflammatory mechanisms. Thus, rosiglitazone could be a relevant drug for patients taking non-steroidal anti-inflammatory drugs (NSAIDs) and at high risk of developing gastric ulceration.

Reduction of asymmetric dimethylarginine in the protective effects of rutaecarpine on gastric mucosal injury

Our recent study has shown that asymmetric dimethylarginine (ADMA) plays an important role in facilitating gastric mucosal injury by multiple factors. To explore whether the protection of rutaecarpine against gastric mucosal injury is related to reduction of ADMA content, a model of ethanol-induced gastric mucosal injury in rats was selected for this study. The ulcer index, the content of ADMA and NO, and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in gastric tissues were measured in vivo after pretreatment with rutaecarpine. The in vitro effect of rutaecarpine on the release of calcitonin gene-related peptide (CGRP) and NO from isolated gastric tissues was also determined. The results showed that ethanol significantly increased the ulcer index, decreased the DDAH activity and the NO level, and elevated the ADMA level, which was attenuated by pretreatment with rutaecarpine (0.6 mg/kg or 1.2 mg/kg). In the isolated gastric tissues, rutaecarpine significantly increased the release of both CGRP and NO; the release of NO, but not CGRP, was abolished in the presence of l-NAME (10(-4) mol/L). The present results suggest that rutaecarpine protects the gastric mucosa against injury induced by ethanol and that the gastroprotection of rutaecarpine is related to reduction of ADMA levels through stimulating the release of CGRP.

Gastroprotective Effects of Melastoma malabathricum Aqueous Leaf Extract against Ethanol-Induced Gastric Ulcer Iin Rats

The gastro-protective effects of the aqueous leaf extract of Melastoma malabathricum was investigated against ethanol-induced gastric mucosal injuries in rats. There were four groups of adult sprague dawley rats, consisting of six rats per group. Macroscopically, oral administration of absolute ethanol to rats that had been pre-treated with only distilled water significantly produced extensive lesions of the gastric mucosa. Oral pre-treatment with either 250 mg kg−1 of M. malabathricum extract, 500 mg kg−1 of M. malabathricum extract, or 20 mg kg−1 of omeprazole 60 minutes before administration of absolute ethanol significantly reduced the formation of gastric mucosal injuries. The observed protection was significant and dose dependent in inhibiting ethanol-induced gastric ulcers. Microscopically, rats that had been pre-treated with only distilled water showed marked damage of the gastric mucosa, induced submucosal edema and leucocytes infiltration. However, animals that had been pre-treated with aqueous leaf extracts or omeprazole showed marked reduction of gastric mucosal damage, reduction of oedema and less leucocyte infiltration of submucosal layer. The results indicated that 500 mg kg-1 aqueous leaf extract of M. malabathricum provided the best protection to the gastric mucosa in rats against ethanol-induced gastric ulcers.

G cells and gastrin in chronic alcohol-treated rats

Numerous reports have described gastric mucosal injury in rats treated with high ethanol concentrations. However, to the best of our knowledge, ultrastructural characteristics of G cells and antral gastrin levels have not been previously reported, either in rats that chronically consumed alcohol or in human alcoholics. The goal of this study was to examine the effect of ethanol consumption (8.5 g/kg) over a 4-month period, under controlled nutritional conditions, on antral and plasma levels of gastrin, ultrastructure of G cells, morphometric characteristics of G cells by stereological methods, and analysis of endocrine cells in the gastric mucosa by immunohistochemistry. The chronic alcohol consumption resulted in a nonsignificant decrease in gastrin plasma levels and unchanged antral gastrin concentrations. A slightly damaged glandular portion of the gastric mucosa and dilatation of small blood vessels detected by histological analysis, suggests that ethanol has a toxic effect on the mucosal surface. Chronic alcohol treatment significantly decreased the number of antral G cells per unit area, and increased their cellular, nuclear, and cytoplasmatic profile areas. In addition, the volume density and diameter of G-cell granules, predominantly the pale and lucent types, were increased, indicating inhibition of gastrin release. Ethanol treatment also decreased the number of gastric somatostatin-, serotonin-, and histamine-immunoreactive cells, except the somatostatin cells in the pyloric mucosa, as well as both G: D: enterochromaffin cells (EC) cell ratios in the antrum and D: ECL cell ratios in the fundus. These results indicate that the change of morphometric parameters in G cells may be related to cellular dysfunction. Our findings also suggest that regulation of G-cell secretion was not mediated by locally produced somatostatin in ethanol-consuming rats, but may involve gastric luminal content and/or neurotransmitters of gastric nerve fibers.

Effect of Culinary-Medicinal Lion's Mane Mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae), on Ethanol-Induced Gastric Ulcers in Rats

The cytoprotective effect of Hericium erinaceus freeze-dried fruiting bodies was investigated against ethanol-induced gastric mucosal injury in rats. Four groups of adult male Sprague Dawley rats were pretreated with distilled water (negative control), 250 mg kg−1 H. erinaceus, 500 mg kg−1 H. erinaceus, and omeprazole (positive control), respectively, before oral induction with absolute ethanol to generate gastric mucosal injury. Overall, rats pretreated with only distilled water suffered extensive hemorrhagic gastric mucosa lesions, whereas pretreatment with H. erinaceus or omeprazole reduced ulceration, with better cytoprotection observed in rats pretreated with omeprazole or 500 mg kg−1 H. erinaceus compared to rats pretreated with 250 mg kg−1 H. erinaceus. Histologically, marked damage was observed in the gastric mucosa, with submucosal edema and leucocyte infiltration in negative-control rats, whereas H. erinaceus-pretreated and positive-control rats had less gastric mucosal damage, decreased edema, and no submucosal leucocyte infiltration. In conclusion, H. erinaceus provided cytoprotection against ethanol-induced gastric ulcers in rats.

Prophylactic Effect of Rebamipide on Aspirin-Induced Gastric Lesions and Disruption of Tight Junctional Protein Zonula Occludens-1 Distribution

Aspirin and nonsteroidal anti-inflammatory agents are known to induce gastroduodenal complications such as ulcer, bleeding, and dyspepsia. In this study, we examined the prophylactic effect of rebamipide, an anti-ulcer agent with free-radical scavenging and antiinflammatory effect, on acidified aspirin-induced gastric mucosal injury in rats. In addition, we investigated the mucosal barrier functions disrupted by aspirin. Oral administration of acidified aspirin resulted in linear hemorrhagic erosions with increasing myeloperoxidase activity and thiobarbituric acid-reactive substance concentrations in the gastric mucosa. Rebamipide suppressed these acidified aspirin-induced gastric lesions and inflammatory changes significantly, and its protective effect was more potent in the case of repeated (twice daily for 3 days) treatment than single treatment before aspirin administration. Immunostaining of zonula occludens (ZO)-1, one of the tight junctional proteins, was strengthened in rat gastric mucosa after repeated administration of rebamipide. In addition, aspirin induced the increasing transport of fluorescine isothiocyanate-labeled dextrans with localized disruption and decreased expression of ZO-1 protein on rat gastric mucosal cell line RGM-1. Rebamipide effectively prevented aspirin-induced permeability changes and disruption of ZO-1 distribution. These results suggest that rebamipide protects against aspirin-induced gastric mucosal lesions by preserving gastric epithelial cell-to cell integrity in addition to the anti-inflammatory effects.

Influence of dl-alpha-tocopherol acetate on indomethacin-induced gastric mucosal injury in rats

1 There is an increasing body of evidence supporting the hypothesis that antioxidants are able to reduce gastric mucosal damage induced by stressors of different origin. The aim of the present study was to investigate the influence of dl-alpha-tocopherol acetate (TA) on indomethacin-induced gastric mucosal injury in rats and a possible role for an anti-oxidative mechanism in the response. 2 TA (25, 50 and 100 mg kg(-1)) was applied intraperitoneally as a pretreatment 1 h before the subcutaneous administration of indomethacin (30 mg kg(-1)). 3 TA reduced the area of indomethacin-induced gastric ulcers, the effect being significant (P < 0.05) at the highest dose of 100 mg kg(-1). 4 Histopathological examination of rat stomach samples demonstrated that TA caused an increase in gastric mucus production and a reduction of the severity of mucosal lesions. 5 The three doses of TA prevented indomethacin-induced elevation of plasma and mucosal malondialdehyde (MDA) levels, which in TA-pretreated rats were not significantly different from the control values. Neither indomethacin treatment nor TA pretreatment had a significant influence on the gastric mucosal levels of reduced glutathione or oxidized glutathione. 6 Our results suggest that the gastroprotective effect of TA is likely to be due to increased mucus production and interference with oxidative stress development as evidenced by the decreased plasma and gastric mucosal MDA.

Protective Effect of a Novel Rice Extract Against Ethanol-Induced Gastric Mucosal Injury in Rat

The aim of this study was to investigate the protective action of rice extract on ethanol-induced mucosal damage in vivo and wound healing of epithelial cells in vitro. Also, the effect of rice extract on gastric mucosal prostaglandin E(2) level, HSP72 expression, gastric acid secretion, and contribution of vanilloid receptor-mediated action was studied. In addition, using cultured gastric mucosal cells (RGM-1), the effect of rice extract on cytoprotection and wound healing of epithelial cells was evaluated. Rice extract significantly reduced gastric mucosal damage produced by ethanol in vivo, and heat treatment (80 degrees C, 3 min) of this agent did not alter its protective effect. Rice extract also protected RGM-1 from ethanol-induced damage in a dose-dependent manner. Rice extract accelerated wound healing of gastric epithelial cells. Our results demonstrate that rice extract could be an alternative ulcer treatment that provides cytoprotection and enhancement of wound healing not dependent on acid secretion, prostaglandin E(2) level, HSP72 expression, or vanilloid receptors.

Inhibition of Neutrophil Activation by Lafutidine, an H2-receptor Antagonist, Through Enhancement of Sensory Neuron Activation Contributes to the Reduction of Stress-Induced Gastric Mucosal Injury in Rats

Sensory neuron activation reduces water-immersion restraint stress (WIR)-induced gastric mucosal injury by inhibiting neutrophil activation through increase in endothelial production of prostacyclin. This study was designed to examine whether lafutidine, which is an H(2)-receptor antagonist and activates sensory neurons, inhibits neutrophil activation, thereby reducing WIR-induced gastric mucosal injury. Lafutidine enhanced WIR-induced increases in gastric tissue levels of calcitonin gene-related peptide (CGRP) and 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, whereas famotidine, another H(2)-receptor antagonist, did not. Such lafutidine-induced increases in gastric tissue levels of 6-keto-PGF(1alpha) were reversed by pretreatment with capsazepine, an inhibitor of sensory neuron activation, CGRP(8-37), a CGRP antagonist, and indomethacin. Lafutidine inhibited acid-induced exacerbation of gastric mucosal injury in animals subjected to WIR by inhibiting neutrophil activation, whereas famotidine did not. Lafutidine synergistically increased CGRP release from isolated rat dorsal root ganglion neurons in the presence of anandamide, but famotidine did not. These observations suggest that lafutidine might reduce WIR-induced gastric mucosal injury not only by inhibiting acid secretion but also by inhibiting neutrophil activation through enhancement of sensory neuron activation.

Transcriptome Analysis for Cytoprotective Actions of Rebamipide against Indomethacin-Induced Gastric Mucosal Injury in Rats

We have reported that rebamipide, a gastroprotective drug, suppresses indomethacin-induced gastric mucosal injury in humans and rats. However, the mechanisms of the cytoprotective actions of rebamipide have not been fully addressed. In the present study, we determined mRNA expression profile of the gastric mucosa treated with indomethacin in rats, and investigated the cytoprotective effects of rebamipide against indomethacin-induced injury with a high-density oligonucleotide array (Rat Toxicology U34 GeneChip array). Gastric epithelial cells were obtained by laser-assisted microdissection. Data analysis was performed with a GeneChip Operating Software, GeneSpring software 7.0, and Ingenuity Pathway Analysis. Among 1,031 probes, the expression of 160 probes (15.5%) showed at least 2.0-fold up-regulation (158 probes) and down-regulation (2 probes) 2 h after indomethacin administration in comparison with the vehicle-treated rats. The pathway analysis of the up-regulated 123 probes identified the network with a highly significant score, which consisted of known clusters of cell death, cancer, and endocrine system disorders. We succeeded in listing 10 genes that were up-regulated by the treatment with indomethacin and that were down-regulated by rebamipide, including growth arrest and DNA damage-induced 45α. In conclusion, we demonstrated that cell death, especially apoptosis, pathway is involved in the pathogenesis of indomethacin-induced gastric mucosal injury, and that inhibition of apoptosis-related genes is possibly important for the cytoprotective effect of rebamipide against this injury.

Role of tumor necrosis factor-α in acute gastric mucosal injury in rats after acute brain trauma

Role of tumor necrosis factor-α in acute gastric mucosal injury in rats after acute brain trauma

Beneficial effects ofFoeniculum vulgareon ethanol-induced acute gastric mucosal injury in rats

To examine the anti-ulcerogenic and antioxidant effects of aqueous extracts of Foeniculum vulgare (FVE) on ethanol-induced gastric lesions in rats. FVE was administered by gavage at doses of 75, 150 and 300 mg/kg, and famotidine was used at the dose of 20 mg/kg. Following a 60 min period, all the rats were given 1 mL of ethanol (80%) by gavage. One hour after the administration of ethanol, all groups were sacrificed, and the gastric ulcer index was calculated; whole blood malondialdehyde (MDA) and reduced glutathione (GSH), serum nitrate, nitrite, ascorbic acid, retinol and beta-carotene levels were measured in all the groups. It was found that pretreatment with FVE significantly reduced ethanol-induced gastric damage. This effect of FVE was highest and statistically significant in 300 mg/kg group compared with the control (4.18 +/- 2.81 vs 13.15 +/- 4.08, P < 0.001). Also, pretreatment with FVE significantly reduced the MDA levels, while significantly increased GSH, nitrite, nitrate, ascorbic acid, retinol and beta-carotene levels. FVE has clearly a protective effect against ethanol-induced gastric mucosal lesion, and this effect, at least in part, depends upon the reduction in lipid peroxidation and augmentation in the antioxidant activity.

Study of some physiological mechanisms mediating the cytoprotective effect of clarithromycin on induced gastric mucosal injury in rats

Study of some physiological mechanisms mediating the cytoprotective effect of clarithromycin on induced gastric mucosal injury in rats

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

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. 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. 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. 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.