Stress-induced Gastric Mucosal Injury Research Articles

Protective effect of dietary nitrate on stress-induced gastric mucosal injury via enhancing blood perfusion in Mongolian gerbils.

Protective effect of dietary nitrate on stress-induced gastric mucosal injury via enhancing blood perfusion in Mongolian gerbils.

Effects of Restraint Water-Immersion Stress-Induced Gastric Mucosal Damage on Astrocytes and Neurons in the Nucleus Raphe Magnus of Rats via the ERK1/2 Signaling Pathway

Restraint water-immersion stress (RWIS) consists of psychological and physical stimulation, and it has been utilized in the research of gastric mucosal damage. It has been shown by previous studies that the nucleus raphe magnus (NRM) is closely involved in the gastrointestinal function, but its functions on the stress-induced gastric mucosal injury (SGMI) have not been thoroughly elucidated to date. Consequently, in this research, we aim to measure the expression of astrocytic glial fibrillary acidic protein (GFAP), neuronal c-Fos, and phosphorylation extracellular signal regulated kinase 1/2 (p-ERK1/2) in the process of RWIS with immunohistochemistry and western blot methods. What is more, we detect the relation between astrocytes and neurons throughout the stress procedure and explore the regulation of the ERK1/2 signaling pathway on the activity of astrocytes and neurons after RWIS. The results indicated that all three proteins expression multiplied following peaked 3h substantially. The SMGI, astrocyte and neuron activity were affected after the astrocytotoxin L-A-aminohexanedioic acid (L-AA) and c-fos antisense oligonucleotide (ASO) injections. After the injection of PD98059, the gastric mucosal injury, astrocyte and neuron activity significantly fell off. These results suggested that RWIS-induced activity of astrocytes and neurons in the NRM may play a significant part in gastric mucosa damage via the ERK1/2 signaling pathway.

Ventromedial hypothalamic nucleus in regulation of stress-induced gastric mucosal injury in rats

Previous studies showed that restraint water-immersion stress (RWIS) increases the expression of Fos protein in the ventromedial hypothalamic nucleus (VMH), indicating the VMH involving in the stress-induced gastric mucosal injury (SGMI). The present study was designed to investigate its possible neuro-regulatory mechanisms in rats receiving either VMH lesions or sham surgery. The model for SGMI was developed by restraint and water (21 ± 1 °C) immersion for 2 h. Gastric mucosal injury index, gastric motility, gastric acid secretion and Fos expression in the hypothalamus and brainstem were examined on the 15th postoperative day in RWIS rats. Gastric mucosal injury in VMH-lesioned rats was obviously aggravated compared to the control. Gastric acidity under RWIS was obviously higher in VMH-lesioned rats than that in sham rats. Meantime, the VMH-lesioned rats exhibited marked increases in the amplitude of gastric motility in the VMH lesions group after RWIS. In VMH-lesioned rats, Fos expression significantly increased in the dorsal motor nucleus of the vagus (DMV), the nucleus of the solitary tract (NTS), the area postrema (AP), the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) in response to RWIS. These results indicate that VMH lesions can aggravate the stress-induced gastric mucosal injury through the VMH-dorsal vagal complex (DVC)-vagal nerve pathway.

Stress, Neuropeptides and Gastric Mucosa.

Exposure of the organism to a hostile stimulus results in a series of coordinated reactions that aim to avoid the aversive effect and maintain or restore homeostasis of the organism. In response to noxious stimuli corticotropin-releasing factor (CRF), the primary mediator of stress responses is released from the paraventricular nucleus resulting in activation of the hypothalamic-pituitary-adrenocortical axis and coordination of the endocrine, autonomic, behavioral and immune responses to stress. Several other neuropeptides, released in a coordinated way are also involved in the regulation of the stress response. However, besides the development of adaptive physiological, beneficial reactions, pathological, non-desired somatic and psychic responses can also develop, among others: gastric mucosal damage, erosion and ulceration. The mechanism of stress-related gastric mucosal injury is not fully understood; both mucosal injurious and protective mechanisms are activated in response to stress. Decreased mucosal circulation due to redistribution of blood flow from the visceral region toward the vital organs seems to be the primary mechanism of gastric mucosal damage. Mucosal hypoperfusion can result in mucosal ischemia, free radical formation and gastric hypomotiliy. On the other hand, several stressrelated neuropeptides, such as CRF, SP, N/OFQ, opioids, oxytocin and prolactin have been reported to inhibit the stress- and other ulcerogenic stimulus-induced mucosal lesions independently on their effect on other stressrelated symptoms. Consequently, neuropeptides released during stress, besides their numerous physiological and pathophysiological functions, may initiate adaptive mechanisms as well as counteract the stress-induced gastric mucosal injury.

Protective effect of hydrogen sulfide against cold restraint stress-induced gastric mucosal injury in rats

Hydrogen sulfide (H2S) is an endogenous gaseous mediator plays a potential role in modulating gastric inflammatory responses. However, its putative protective role remains to be defined. The present study aimed to evaluate role of the exogenously released and endogenously synthesized H2S in cold restraint stress (CRS)-induced oxidative gastric damage in rats. Rats were restrained, and maintained at 4°C for 3h. The H2S donor, sodium hydrosulfide (NaHS) (60μmol/kg) was injected intraperitoneally (i.p.) before CRS. Our results revealed that NaHS pretreatment significantly attenuated ulcer index, free and total acid output, and pepsin activity in gastric juice along with decreased gastric mucosal carbonyl content and reactive oxygen species production. This was accompanied by increased gastric juice pH and mucin concentration in addition to restoring the deficits in the gastric reduced glutathione, catalase as well as superoxide dismutase enzyme activities. NaHS pretreatment markedly reduced the serum level of tumor necrosis factor (TNF-α) and myeloperoxidase activity compared to CRS-non-treated. Moreover, NaHS preadministration significantly abrogated the inflammatory and the deleterious responses of gastric mucosa in CRS. The protective effects of H2S were confirmed by gastric histopathological examination. However, pretreatment with the H2S-synthesizing enzyme, cystathionine-gamma-lyase inhibitor, beta-cyano-L-alanine (50mg/kg, i.p.) reversed the gastroprotection afforded by the endogenous H2S. Collectively, our results suggest that H2S can protect rat gastric mucosa against CRS-induced gastric ulceration possibly through mechanisms that involve anti-oxidant and anti-inflammatory actions alongside enhancement of gastric mucosal barrier and reduction in acid secretory parameters.

Pure tocotrienol concentrate protected rat gastric mucosa from acute stress-induced injury by a non-antioxidant mechanism

Stress has been implicated as a risk factor of various major health problems, such as stress-induced gastric mucosal injury. This study was performed to investigate the action of a pure preparation of tocotrienol (T3) concentrate, made up of 90% δ-tocotrienol and 10% γ-tocotrienol, on gastric injury of rats induced by water-immersion restraint stress (WIRS). Fourteen male Sprague-Dawley rats (200-250 g) were divided into two equal groups: a control group and a treated group. The treatment group received T3 concentrate at 60 mg/kg body weight daily for 28 days. The body weights of rats were recorded daily before the treatment was given. At the end of the treatment period, all rats were subjected to WIRS for 3.5 hours, following which the rats were euthanized. The stomachs were isolated and opened along the greater curvature for the examination of lesions and measurements of gastric malondialdehyde (MDA) and prostaglandin E₂ (PGE₂) contents. The mean gastric mucosal lesion index in the treated rats was significantly lower than that in the control rats. This suggests that the T3 concentrate has the ability to confer protection to the gastric mucosa against gastric injury induced by acute stress. No significant difference was observed for changes in body weight before and after the treatment. The gastric PGE2 content in both groups was comparable. However, the gastric MDA content was significantly higher in the treated group compared to the control group, indicating that the T3 supplementation was not able to reduce the lipid peroxidation process. This study concludes that the T3 concentrate has the ability to protect the gastric mucosa from stress-induced injury by a non-antioxidant mechanism.

W1715 Correlation of Heat Shock Proteins Expression to Gender Difference in Development of Stress-Induced Gastric Mucosal Injury in Rats

W1715 Correlation of Heat Shock Proteins Expression to Gender Difference in Development of Stress-Induced Gastric Mucosal Injury in Rats

Correlation of Heat Shock Protein Expression to Gender Difference in Development of Stress-Induced Gastric Mucosal Injury in Rats

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.

Effects of Artichoke Leaf Extract on Acute Gastric Mucosal Injury in Rats

The present study was designed to clarify the effects of an ethanol extract of artichoke leaf on acute gastric mucosal injury in rats. Oral administration of artichoke leaf extract dose-dependently prevented absolute ethanol-induced (125-500 mg/kg) or restraint plus water immersion stress-induced gastric mucosal injury (1000-2000 mg/kg). The artichoke leaf extract contains 1% cynaropicrin and 0.8% chlorogenic acid as main components and 70% dextrin as a vehicle. Cynaropicrin at doses of 1/100 of artichoke leaf extract [ethanol-induced mucosal injury: 5 mg/kg, per os (p.o.); stress-induced mucosal injury: 20 mg/kg, p.o.] also prevented gastric mucosal injury in both animal models. However, dextrin and chlorogenic acid at doses contained in the leaf extract were ineffective in both models. When artichoke leaf extract was given orally to normal rats, it (500-2000 mg/kg, p.o.) dose-dependently increased gastric mucus content. In addition, it (125-500 mg/kg, p.o.) dose-dependently prevented the decrease in gastric mucus content by absolute ethanol. When the effects of artichoke leaf extract on basal gastric acid secretion in rats were evaluated, it (500-2000 mg/kg, p.o.) dose-dependently increased the volume of gastric juice in normal rats. However, it was ineffective in decreasing basal gastric acid secretion in normal rats. These results indicate that artichoke leaf extract is effective against acute gastritis and its beneficial effect is due to that of cynaropicrin. The gastric mucus-increasing action of artichoke leaf extract may be, at least in part, related to the anti-gastritic action of the extract.

Restoring Erectile Function by Antioxidant Therapy in Diabetic Rats

Diabetes mediates an increase in reactive oxygen species that can lead to impaired endothelial function, decreased smooth muscle in the diabetic corpus cavernosum and increased apoptosis. We hypothesized that antioxidant therapy may restore erectile function by inhibiting apoptosis in diabetic rat crura. A total of 40 male Sprague-Dawley rats were randomized to 5 groups of 8 each, including healthy controls, rats with diabetes, and rats with diabetes with the antioxidant tempol (4-hydroxytetramethyl-piperidine-1-oxyl) (Sigma-Aldrich), with insulin, and with tempol and insulin. Intracavernous pressure was measured for functional analysis. Smooth muscle and collagen fiber levels in the rat penile corpus cavernosum were assessed by hematoxylin and eosin, and Masson's trichrome staining. Endothelial cells were assessed by CD31 staining. Reactive oxygen species related genes were analyzed by cDNA microarray. We confirmed mRNA and protein expression profiles for these genes in diabetic and treated rats using real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. TUNEL assay was done to analyze apoptosis status. Intracavernous pressure in diabetic rats was significantly decreased vs controls. After treatment with tempol or insulin alone intracavernous pressure was significantly increased compared to that in untreated diabetic rats. In the diabetic group mean smooth muscle area significantly decreased but was restored after combined tempol and insulin. Endothelial cell area in diabetic rats significantly decreased and was not restored by any treatments. However, apoptosis was restored to normal by combined insulin and tempol. Of 84 reactive oxidative stress and antioxidant genes 32 were identified specific to diabetic rats compared to healthy controls. UCP3 expression was significantly increased in diabetic rats and normal levels were restored by all treatments. To our knowledge this is the first report that tempol and insulin can restore erectile function in diabetic rats by inhibiting apoptosis.

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.

Methamphetamine protects against stress-induced gastric mucosal lesions in mice

Stress-induced gastric mucosal injury is a common clinical entity. On the other hand, abuse of methamphetamine (MA) represents a growing social problem. MA users are frequently in stressful situations. In this study, we examined the effects of MA on gastric injury, corticosterone level and immunomodulation using a water-immersion restraint stress (WRS) mouse model that is well known to induce gastric lesions. Mice were randomly divided into five groups: (1) the normal group, (2) the 3 hour (3 h)-WRS group, (3) the 6 hour (6h)-WRS group, (4) the MA (3 mg/kg) plus 6 h-WRS group and (5) the MA (30 mg/kg) plus 6 h-WRS group. As expected, most animals examined (above 90%) showed gastric injury after the WRS exposure. However, administration of MA at both 3 and 30 mg/kg resulted in significant suppression of the injury. The corticosterone levels were increased by exposure to the stress and/or MA, but there was no difference between these groups. The levels of the serum cytokines IL-6, IL-10 and TNF were increased by WRS, and were markedly increased by MA plus WRS; in particular, the level of IL-6 was synergistically increased. On the contrary, the level of IL-1β was significantly decreased by WRS and MA plus WRS. This is the first report showing the protective effect of MA on stress-induced gastric injury, although further study is necessary to resolve the mechanism of MA-driven suppression of the injury.

Insulin-like growth factor-I reduces stress-induced gastric mucosal injury by inhibiting neutrophil activation in mice

Objective We previously reported that activated neutrophils are critically involved in the development of stress-induced gastric mucosal injury in mice. Caspase activation plays an important role in the pathogenesis of tissue injury by activating neutrophils through an increase in the expression of endothelial monocyte-activating polypeptide-II (EMAP-II), a chemoattractant for neutrophils. Since insulin-like growth factor-I (IGF-I) inhibits caspase activation, it is possible that IGF-I reduces gastric mucosal injury by inhibiting neutrophil activation. In the present study, we examined this possibility in mice subjected to water-immersion restraint stress (WIR). Design Mice were intraperitoneally administered with IGF-I or vehicle before being subjected to WIR. Gastric mucosal injury, gastric myeloperoxidase (MPO) activity, the immunofluorescence intensity of MPO, caspase-3 activity, number of apoptotic cells, EMAP-II expression and activation of Akt and glycogen synthase kinase-3β (GSK-3β) in gastric mucosa were determined in mice subjected to WIR. Neutropenia was induced by administration of methotrexate (MTX). Results Administration of IGF-I at dosages higher than 200 μg/kg significantly reduced gastric mucosal injury and inhibited increases in gastric MPO activities after 8 h of WIR. Administration of MTX also reduced the gastric mucosal injury as well as inhibiting increases in both gastric mucosal MPO activities and circulating neutrophil number. IGF-I (500 μg/kg) inhibited the increases in both gastric MPO activity and the immunofluorescence intensity of MPO observed in the gastric mucosa, but had no effect on the increase in circulating neutrophil number after 8 h of WIR. It also markedly blunted WIR-induced increases in caspase-3 activities and the number of apoptotic cells in the gastric mucosa after 8 h of WIR. Gastric expression of EMAP-II was markedly increased at 8 h after starting WIR and this increase was inhibited by IGF-I administration. Administration of IGF-I enhanced WIR-induced phosphorylation of Akt and GSK-3β in the gastric mucosa. Conclusion These observations indicate that IGF-I reduces stress-induced gastric mucosal injury by inhibiting gastric accumulation of neutrophils through inhibition of caspase-3-mediated EMAP-II activation. Furthermore, IGF-I might inhibit caspase-3 activation through Akt/GSK-3β signaling.

Activation of p38 MAPK by Reactive Oxygen Species Is Essential in a Rat Model of Stress-Induced Gastric Mucosal Injury

Stress ulceration is a common complication in critically ill patients and can result in significant upper gastrointestinal bleeding associated with a high morbidity and mortality. At present, little is known of the molecular mechanisms underlying the incidence of this type of gastric damage. In the present study, we investigated the temporal activation of the redox-sensitive p38 signaling transduction cascade and its roles in a well-defined experimental model of cold immobilization stress-induced gastric ulceration. Exposure of Sprague-Dawley rats to 6 h of cold immobilization stress led to a rapid activation of p38 in the gastric mucosa at as early as 15 min after stress, and this activation was maximal after 1.5 h of stress and still persisted until the end of stress. Selectively blocking p38 by pretreatment with SB 239063, a potent and selective p38 inhibitor, suppressed the stress-promoted TNF-alpha, IL-1beta, and CINC-1 production and then prevented the subsequent neutrophil infiltration, gastric mucosal epithelial necrosis and apoptosis, and the ulcerative lesions formation. Prior administration of the free radical scavengers, tempol and N-acetyl-L-cysteine, abolished the stress induction of p38 activation and the resulting mucosal inflammation and gastric injury. These results demonstrate that reactive oxygen species-mediated p38 activation plays an essential role in the pathogenesis of stress-induced gastric inflammatory damage in the rat model of cold immobilization stress. Our findings suggested that inhibition of p38 activation might be a potential strategy for the prophylaxis and treatment of stress ulceration.

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.

The protection of recombinant human activated protein C on acute gastric mucosal lesion in rats

目的 探讨重组人活化蛋白C(rhAPC)对急性胃黏膜损伤的保护机制.方法 SD大鼠24只,随机分为四组:A组为正常组,B组为模型组,C组为rhAPC预处理组,D组为生理盐水对照组.采用浸水束缚应激(WRS)的方法制备大鼠急性胃黏膜损伤的模型,C组在WRS开始前半小时通过鼠尾静脉注入rhAPC(100 μg/kg),D组在同一时间点注入同等量的生理盐水.计数各组大鼠胃黏膜溃疡指数(UI).分离胃黏膜上皮细胞,并制成细胞浓度为1×106/ml的单细胞悬液,加入荧光染料DiOC6,上流式细胞仪检测胃黏膜线粒体跨膜电位.采用ELISA法检测各组血清中肿瘤坏死因子(TNF)-α、白介素(IL)-6的浓度.结果 B组胃黏膜UI,血清TNF-α、IL-6的浓度均较A组明显升高(P＜0.001),胃黏膜线粒体跨膜电位较A组明显下降(P＜0.001).C组胃黏膜UI,血清TNF-α、IL-6的浓度均较B组显著下降(P＜0.001),胃黏膜线粒体跨膜电位较B组显著升高(P＜0.001).结论 rhAPC可抑制TNF-α、IL-6的释放,抑制线粒体跨膜电位降低,从而对胃黏膜急性损伤起保护作用。

This Month in Gastroenterology

This Month in Gastroenterology

Estrogen and isoflavone attenuate stress-induced gastric mucosal injury by inhibiting decreases in gastric tissue levels of CGRP in ovariectomized rats

We have previously reported that CGRP plays a critical role in the reduction of stress-induced gastric mucosal injury by increasing gastric prostacyclin (PGI(2)) levels in rats. Estrogen has been shown to increase the production of CGRP in sensory neurons. Isoflavone has estrogen-like effects and is referred to as a phytoestrogen. Thus, we hypothesized that estrogen and isoflavone might inhibit ovariectomy (OVX)-induced decreases in gastric tissue levels of CGRP, thereby attenuating gastric mucosal injury. We examined these possibilities in the present study. The administration of estradiol and isoflavone for 4 wk completely reversed OVX-induced decreases in CGRP mRNA levels of dorsal root ganglion neurons (DRGs) in rats. OVX-induced decreases in gastric tissue levels of CGRP and 6-keto-PGF(1alpha), a stable metabolite of PGI(2), in rats were reversed by estradiol and isoflavone. Water-immersion restraint stress (WIR)-induced increases in gastric tissue levels of CGRP and 6-keto-PGF(1alpha) were inhibited in ovariectomized rats. This inhibition was completely reversed by estradiol and was partially, but significantly, reversed by isoflavone. WIR-induced gastric mucosal injury was exacerbated by OVX, which was reversed by estradiol and isofolavone. In vitro experiments using DRGs isolated from rats demonstrated that neither estradiol nor isoflavone enhanced CGRP release from DRGs, but the former enhanced it in the presence of anandamide, an endogenous agonist for vanilloid receptor-1. These observations suggest that estrogen and isoflavone might inhibit OVX-induced decreases in CGRP levels in DRGs by promoting transcription, thereby contributing to the attenuation of stress-induced gastric mucosal injury in OVX 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.

Regulation of Inflammatory Responses by Sensory Neurons: Molecular Mechanism(s) and Possible Therapeutic Applications

Capsaicin-sensitive sensory neurons are nociceptive neurons that release calcitonin gene-related peptide (CGRP) on activation. Since CGRP has potent vasodilatory activity, it has long been considered to be involved in aggravation of inflammation such as tissue hyperemia and edema. However, since ablation of the sensory fibers can result in a marked increase in the severity of inflammation and reperfusion-induced tissue inflammatory responses are enhanced in congenital CGRP-knockout mice, the sensory neurons have been shown to play a role in the maintenance of tissue integrity by regulating local inflammatory responses. We demonstrated in rodents that stimulation of sensory neurons reduces hypertension, stress-induced gastric mucosal injury, reperfusion-induced liver injury, and endotoxin-induced shock responses by attenuating inflammatory responses such as increases in both tissue levels of tumor necrosis factor (TNF) and tissue accumulation of neutrophils. Attenuation of inflammatory responses by sensory neuron activation can be explained mainly by CGRP-induced increase in the endothelial production of prostacyclin (PGI(2)). Since inflammatory responses are critically involved in the development of a wide variety of diseases, pharmacological stimulation of sensory neurons might contribute to treatment of various pathologic conditions. In this review, the authors describe molecular mechanism(s) by which sensory neuron activation inhibits TNF production, thereby attenuating inflammatory responses. Furthermore, the authors discuss some clinically useful therapeutic agents that are capable of activating sensory neurons and raise the possibility that pharmacological stimulation of sensory neurons is the new paradigm for future therapeutic strategies.