Peripheral corticotropin-releasing hormone may protect the gastric musosa against indometacin-induced injury through involvement of glucocorticoids.

The hypothalamic-pituitary-adrenocortical (HPA) system is a key hormonal branch of the brain-gut axis in stress and corticotropin-releasing hormone (CRH) is a principal stimulator of the HPA system. According to our finding activation of the HPA system has gastroprotective role in stress and CRH may protect the gastric mucosa against stress-induced injury through involvement of glucocorticoids. To extend this idea to indomethacin-induced gastric injury in the present work we studied whether CRH may protect the gastric mucosa against ulcerogenic action of indomethacin (IM) through involvement of glucocorticoids. CRH administration (1.25 µg/kg and 2.5 µg/kg, i.p.) markedly, dose-dependently, increased plasma corticosterone level and significantly, dose-dependently, suppressed the occurrence of gastric erosion induced by IM (35 mg/kg, s.c.) in conscious rats. To estimate the role of glucocorticoids in CRH-induced gastroprotection, the effect of CRH (1.25 µg/kg) on the IM-induced gastric erosion was studied after acute reduction of corticosterone release by metyrapone (30 mg/kg, i.p., 30 min before CRH administration) or by CRH receptor type 1 antagonist NBI 27914 (10 mg/kg, i.p., 15 min before CRH administration) and also after occupation of glucocorticoid receptors by their antagonist RU-38486 (20 mg/kg, i.p., 2 h before CRH administration). The effects were compared with those in control rats without acute reduction of corticosterone release or occupation of glucocorticoid receptors. Both metyrapone and NBI 27914 injected shortly before CRH administration caused an inhibition of CRH-induced corticosterone response and prevented protective effect of CRH on the gastric mucosa against the IM-induced erosion. The gastroprotective effect of CRH was also eliminated by the pretreatment with glucocorticoid receptor antagonist RU-38486. The results obtained suggest that exogenous CRH may protect the gastric mucosa against IM-induced gastric injury through involvement of glucocorticoids.

Influence of forced treadmill and voluntary wheel running on the sensitivity of gastric mucosa to ulcerogenic stimuli in male rats.

Physical activity is crucial for maintaining health. Here we investigated the preconditioning effects of exercise on the vulnerability of gastric mucosa to ulcerogenic action of indomethacin (IM, 35 mg/kg, s.c.) or cold-restraint stressor (CR, 3 h, 10°C) in male rats. Single or repeated (5 days) training was used either voluntarily (2 h/day, wheel running) or in a forced way (treadmill). The intensity of the later was either "moderate" (9 m/min, 15 min) or "intensive" (15 m/min, 30 min). All protocols were confirmed by elevated plasma corticosterone and increased tail flick latencies (analgesia). IM-induced ulceration was attenuated by single intensive forced exercise, repeated voluntary and moderate forced exercise. On the contrary, single 2 h voluntary session aggravated the IM-induced ulceration. The ulcerogenic effect of CR was aggravated by single and repeated voluntary and single intensive forced exercise, while repeated moderate forced running was gastroprotective. Single moderate forced running did not influence the ulcerogenic effect of both agents. The results suggest that physical training might have both beneficial and harmful effects on the vulnerability of gastric mucosa to ulcerogenic stimuli depending on the nature of ulcerogenic stimulus as well as the intensity of running and its duration.

Effects of stress preconditioning on vulnerability of gastric and small intestinal mucosa to ulcerogenic action of indomethacin in rats.

The preconditioning effect of a mild stressor can reduce the ulcerogenic effect of a severe stressor on the gastric mucosa. The aim of the study was to investigate the effect of preconditioning stress on the gastric and the small intestinal injury caused by a single injection of indomethacin (IM) in conscious rats. Preliminary fasting (24 hours) rats were subjected IM administration (35 mg/kg, subcutaneously) with preconditioning stress (30 min cold-restraint at 10°C and further 1 hour keeping in cages at room temperature) or without stress. Plasma corticosterone level, heart rate (HR), blood pressure (BP) and somatic pain sensitivity (tail flick latency) were measured under circumstances of the gastrointestinal IM-induced injury in preliminary stressed and non-stressed rats. IM administration induced formation of gastric erosions well visible 4 hours after its injection. The healing of gastric erosions for 48 hours was accompanied by the development of a small intestinal injury. Corticosterone levels were elevated under formation of gastric erosions (4 hours after IM injection) but decreased following their healing (24 and 48 hours IM injection). Cold-restraint stress caused corticosterone rise 30 min after its onset. IM-induced gastrointestinal injury resulted in an increase of tail flick latencies (somatic hypoalgesia) and gradual decrease of systolic BP and increase of the HR. Stress preconditioning attenuated IM-induced gastric erosions as well as small intestinal injury 4 and 24 hours after its injection, respectively. The preconditioning also resulted in elimination of somatic hypoalgesia 4 hours after IM, but didn't influence an appearance of somatic hypoalgesia 24 and 48 hours after IM. Preconditioning stress recovered the HR and systolic BP (48 hours after IM). Elevated corticosterone level could be observed only in the 4th hour, but not in the 24th and 48th hours after IM administration. Thus, the data suggest that preconditioning stress reduces the vulnerability of the gastric and the small intestinal mucosa to ulcerogenic action of IM, stabilizes the hemodynamic parameters and normalizes somatic pain sensitivity.

Vulnerability of gastric and small intestinal mucosa to ulcerogenic action of indomethacin in C57/BL6/J mice and transient receptor potential channel vanilloid type 1 knockout mice.

Capsaicin-sensitive sensory nerves are densely distributed in the gastrointestinal system and involved in maintenance of gastrointestinal mucosal integrity. capsaicin selectively stimulates nociceptive neurons and its action is mediated through the transient receptor potential channel vanilloid type 1 (TRPV1) receptor. Activation TRPV1 receptors that play a fundamental role in pain signaling, may also exert protective effects against gastrointestinal injury. The present study was performed to investigate and compare the vulnerability of gastric as well as small intestinal mucosa to ulcerogenic action of indomethacin (IM) in mice with genetically deleted TRPV1 receptor (TRPV1 KO) and in C57/BL6/J mice. IM-induced injury was assessed macroscopically as well as histologically; the somatic pain sensitivity was estimated by tail flick latency (tail flick test); plasma corticosterone levels and body weight were also monitored. A single IM administration (35 mg/kg, subcutaneously) into pre-starving (24 h) mice caused the formation of gastric erosions 4 h later and, then, after refeeding, induced formation of the small intestinal injury which was visible 24, 48, 72 h after IM administration. Although IM-induced gastrointestinal injury was detectable in both C57/BL6/J and TRPV1 KO mice, area of gastric damage was greater in C57/BL6/J than in TRPV1 KO mice, whereas the small intestinal injury (48 and 72 h after IM injection), on the contrary, prevailed in TRPV1 KO mice compared to C57/BL6/J mice. In 24 h after IM injection, the total area of intestinal injury did not differ in C57BL6/J and TRPV1 KO mice, however histological score was higher in TRPV1 KO mice than C57BL6/J mice. TRPV1 KO mice showed the increased tail flick latencies and the lacking IM-induced corticosterone rise. The data suggest that in TRPV1 KO mice the gastric mucosa is less vulnerable to ulcerogenic action of IM compared to C57/BL6/J mice, however, their small intestinal mucosa, on the contrary, is more vulnerable to the ulcerogenic action than in C57/BL6/J mice.

[TRANSFORMATION OF GASTROPRO- TECTIVE EFFECT OF STRESS IN PROULCEROGENIC CONSEGUENCE: DEVELOPMENT OF EXPERIMENTAL MODELS].

The present work was focused on the development of experimental models, in which we can observe the transformation of gastroprotective effect of stress into the proulcerogenic one. For this aim the effect chronic stress on the formation of indomethacin (35 mg/kg)-induced gastric erosion or cold restrain (10 or 6 °C)-induced gastric erosion was investigated in rats. For chronic stress rats were repeatedly restrained for 14 days daily (1 h or 4 h mild restrain or 1 h intensive restrain) and examined on day 14. Mild restraining didn't influence on gastric mucosa. In case of intensive restrain, the protective effect of chronic stress on the gastric mucosa was found. In order to avoid the adaptation to the daily stressor of the same modality, we subjected the rats on a daily for 14 days to unpredictable stressors of various modalities. Even in the case of strong unpredictable chronic stress we observed its gastroprotective effect if the indomethacin or cold restrain (10 °C) were used as ulcerogenic factors. The proulcerogenic effect of unpredictable stress was observed only if cold restrain at 6 °C was used as ulcerogenic factor. In conclusion, the findings again support the idea about the gastroprotective effect of stress, even in regards to chronic stress and demonstrate experimental models of transformation gastroprotective effect of stress to ulcerogenic one.

Involvement of corticotropin-releasing factor receptors type 2, located in periaquaductal gray matter, in central and peripheral CRF-induced analgesic effect on somatic pain sensitivity in rats.

Corticotropin-releasing factor (CRF) is involved in the regulation of pain sensitivity and can induce an analgesic effect in animals and humans. The periaqueductal gray matter (PAGM) of the midbrain is one of the key structures of the antinociceptive system. The aim of the study was to investigate the involvement of CRF receptor type 2 (CRF-R2 receptors), localized in the PAGM, in the analgesic effect caused by central or systemic CRF on somatic pain sensitivity in conscious rats. Somatic pain sensitivity was tested by a tail flick test (measuring tail flick latency induced by tail's thermal stimulation). The involvement of CRF-R2 receptors was studied by administering the selective antagonist astressin2-B into the PAGM. Both peripheral and central CRF administration caused an increase in tail flick latencies (analgesic effect). Administration of astressin2-B into the PAGM attenuated the analgesic effect induced by the central as well as systemic CRF administration. The results suggest that one of the mechanisms of the CRF-induced analgesic effect may be mediated by CRF-R2 receptors located in PAGM.

[The Influence of Glucocorticoids on the Healing Processes in the Gastric Mucosa].

In this review, we analyzed the data of literature about the glucocorticoid influences on the gastric erosion and ulcer healing. The data show that multiple injections of glucocorticoids at pharmacological doses delay gastric erosion and ulcer healing. However, according to experimental results endogenic glucocorticoids, on the contrary, play significant role in maintenance of gastric mucosal integrity. Thus, glucocorticoids may have dual effect on healing of gastric injury: contribute to healing process or delay them. The initial glucocorticoid action is physiological and consists in a participation in healing processes what is considered as component gastroprotective action of these hormones. During a long-lasting action of glucocorticoids, the physiological effect can be transformed into pathological one, delaying erosion and ulcer healing, and this contributes to the ulcerogenic action of glucocorticods.

[MECHANISMS OF PROULCEROGENIC EFFECT OF CORTISOL AT PHARMACOLOGICAL DOSE ON THE GASTRIC MUCOSA].

In this study, we investigated the mechanisms of proulcerogenic effect of Cortisol at pharmacological dose on the gastric mucosa in rats. Cortisol (300 mg/kg, ip, single) was administered 1, 3, 5, 7 and 30 days before ulcerogenic stimulus (indomethacin, 35 mg/kg, sc). The gastric mucosa integrity, blood corticosterone, glucose levels, the body weight and the thymus and spleen weight were tested 4 h after indomethacin or at appropriate day after cortisol treatment (in rats without indomethacin). Cortisol treatment resulted in an increase in blood glucose levels with a maximum at day 3, decrease in the body weight and weight of the thymus and the spleen. A deficiency of glucocorticoids in the blood and an increase in indomethacin-induced gastric injury were observed 7 days after the cortisol pretreatment. At the same time all parameters did not differ from controls 30 days after cortisol pretreatment. The results suggest that cortisol at a pharmacological dose may cause proulcerogenic action on the gastric mucosa through a long-lasting maintenance of blood glucose levels accompanied by the signs of catabolic effect and through a deficiency of glucocorticoid production.

[GASTROPROTECTIVE EFFECT OF CORTICOTROPIN-RELEASING FACTOR IN STREPTOZOTOCIN-INDUCED DIABETIC RATS].

The results of our previous studies suggest that corticotropin-releasing factor (CRF) protects the gastric mucosa of rats against stress- and indomethacin-induced gastric injury. In the present study, we investigated whether CRF may protect gastric mucosa against indomethacin-induced gastric injury on diabetic rats. Diabetes was induced by streptozotocin (70 mg/kg) 14 days before indomethacin injection. CRF (2.5 |xg/kg) and CRF receptor antagonists were injected 15 min before indomethacin. The diabetes development resulted in the aggravation of gastric mucosal erosion produced by indomethacin. Intraperitoneal CRF administration caused pronounced gastropro-tective action in control as well as diabetic rats that resulted in significant attenuation of indomethacin-induced gastric erosion. Nonselective antagonist CRF receptors astressin as well as selective antagonists of CRF1 and CRF2 receptors (NBI 27914, 10 mg/kg or astressin2-B, 50 |xg/kg, respectively) aggravated ulcerogenic effect of indomethacin in diabetic rats. The results obtained suggest that exogenous and endogenous CRF may protect the gastric mucosa of diabetic rats against indomethacin-induced injury through CRF1 and CRF2 receptors.

[Role of the Periaqueductal Gray Matter of the Midbrain in Regulation of Somatic Pain Sensitivity During Stress: Participation of Corticotropin-Releasing Factor and Glucocorticoid Hormones].

Periaqueductal gray matter of the midbrain (PAGM) plays a crucial role in the regulation of pain sensitivity under stress, involving in the stress-induced analgesia. A key hormonal system of adaptation under stress is the hypothalamic-pituitary-adrenocortical (HPA) axis. HPA axis's hormones, corticotropin-releasing factor (CRF) and glucocorticoids, are involved in stress-induced analgesia. Exogenous hormones of the HPA axis, similarly to the hormones produced under stress, may cause an analgesic effect. CRF-induced analgesia may be provided by glucocorticoid hormones. CRF and glucocorticoids-induced effects on somatic pain sensitivity may be mediated by PAGM. The aim of the review was to analyze the data of literature on the role of PAGM in the regulation of somatic pain sensitivity under stress and in providing of CRF and glucocorticoid-induced analgesia.

A wider view on gastric erosion: detailed evaluation of complex somatic and behavioral changes in rats treated with indomethacin at gastric ulcerogenic dose.

OBJECTIVE: Gastric erosion is widespread side effect of nonsteroidal anti-inflammatory drugs. To examine the complexity of the brain-gut axis regulation, indomethacin-induced gastric erosion formation was studied in connection with somatic and behavioral changes. METHODS: During a constant telemetric recording of heart rate, body temperature, and locomotion of male rats we examined the effects of 24 h fasting, indomethacin (35 mg/kg s.c.) injection, and refeeding at 4 h. Behavior was analyzed on elevated plus maze (EPM) at 24 h and somatic changes at 72 h. RESULTS: Gastric erosion developed 4 h after indomethacin injection, healed 72 h later contrasted by large injury in the small intestine. As classical signs of chronic stress, body and thymus weight were reduced while adrenal weight was enhanced 72 h after indomethacin injection. Fasting by itself changed all telemetrically recorded parameters with most prominent decrease in heart rate. Indomethacin induced similar diminishing effects with earliest and strongest temperature decrease. As a sign of more anxious phenotype locomotion reducing effect of indomethacin injection was detected on EPM. The EPM-induced temperature elevation was missing in indomethacin-treated animals. CONCLUSIONS: Fasting by itself induce somatic changes, which can make the animals more vulnerable to ulcerogenic stimuli. Development of indomethacin-induced gastrointestinal lesions happened in parallel with disturbances of heart rate, core body temperature, and chronic stress-like somatic changes as well as anxiety-like behavior. We have to be more aware of the existence of the brain-gut axis and should study changes in the whole body rather than focusing on a specific organ. elevated plus maze.

[Somatic pain sensitivity under indometacin induced gastric and small intestinal injury in rats].

The aim was to study the effect of indometacin (IM) induced gastrointestinal injury on somatic pain sensitivity in awake rats. IM was administered at the ulcerogenic dose (35 mg/kg, s. c.) to fasted (24 h) and fed rats. Somatic pain sensitivity was evaluated using a tail flick test. Latency time was measured under conditions of the formation of gastric erosion (1 - 4 h after IM injection) as well as small intestinal injury (24, 48 and 72 h after IM injection). IM administration caused the gastric erosion formation only in fasted rats (4 h after the administration) and the small intestinal injury in both fasted and fed rats (24, 48, 72 h after the administration). Indomethacin-caused gastric and small intestinal injury resulted in an increase in tail flick latency. We did not observe any changes in tail flick latency in IM-treated rats without significant gastrointestinal injury. The gastrointestinal injury was accompanied by signs of chronic stress: long-lasting increase in corticosterone blood level, adrenal hypertrophy, thymus involution, and loss of body weight. Thus, the IM-induced gastrointestinal injury formation resulted in somatic pain inhibition in awake rats.

[Dual effects of glucocorticoids on the gastric mucosa].

In this review we systematise and analyze data of literature about the effect of glucocorticoids on the gastric mucosa. There are convincing results that show the adaptive gastoprotective nature of endogenous glucocorticoids, which are produced during acute stress-induced activation of the HPA axis. The role glucocorticoid hormones play in the effect of chronic stress remains little-studied. We have seen that after single administration of glucocorticoids, there can arise gastroprotective and ulcerogenic effects. Although. the question about the effect of therapy using glucocorticoid hormones on gastric ulceration is being debated, the data confirm the ulcerogenic influence that large doses of these hormones have on experimental animals. The initial gastroprotective effect that glucocorticoid hormones have, even after their single administration can be transformed into an ulcerogenic effect with a prolongation of the hormonal action, but not of the hormone dose. We are discussing the possible mechanism behind the transformation.

[Effect of corticotropin releasing factor(CRF) on somatic pain sensitivity in conscious rats: involvement of CRF1 and CRF2 receptors].

Corticotropin-releasing factor (CRF) is involved in the regulation of pain sensitivity and can cause an analgesic effect in animals and humans. The aim of the study was to investigate the involvement of CRF1 and CRF2 receptors in CRF-induced analgesic effect (after intraperitoneal injection) on somatic pain sensitivity in conscious rats. Somatic pain sensitivity was tested by tail flick latency (tail flick test). The involvement of CRF1 and CRF2 receptors was studied by their selective antagonists NBI 27914 and astressin 2B, respectively. Systemic administration of CRF caused an increase in tail flick latency (analgesic effect). Pretreatment with NBI 27914 or astressin 2B eliminated CRF-induced analgesic effect. Besides, NBI 27914, but not astressin 2B, increased basal tail flick latency. The data obtained indicate that the analgesic effect can be mediated by both CRF1 and CRF2 receptors. CRF-1 receptor, in contrast to the CRF2 receptors, may be involved in the regulation of the basal level of pain sensitivity.

[Contribution of glucocorticoid hormones to gastroprotection].

The fact that the disturbance of the normal stress reaction by the elimination of the hypothalamic-pituitary-adrenocortical (HPA) axis's functioning leads to negative effects on the body such as the development and aggravation of diseases proves that stress plays a leading role in maintaining the physical health of the body. Here we demonstrate this on the base of the results of our experimental studies related with gastric ulceration. The results show that the reduction in the stress-induced corticosterone release, or its actions, aggravates stress-caused gastric erosion. The data do not support the traditional paradigm about ulcerogenic role of glucocorticoids in stress and suggest that glucocorticoids released during acute activation of the HPA axis are naturally occurring gastroprotective factors.

[Metyrapone effect on gastroprotective action of corticotropin-releasing factor administered centrally against indomethacin-induced gastric injury].

In the present study, we investigated whether corticotropin-releasing factor (CRF) injected into the brain induces protection against indomethacin-caused gastric injury and the role of glucocorticoids in the protection. Gastric injury was caused by indomethacin (35 mg/kg, s.c.) in preliminary (24 h) fasted rats. CRF (10 microgram/rat, i.c.v.) was injected 30 min before administration of indomethacin. The participation of glucocorticoids was studied by metyrapone pretreatment (30 mg/kg, i.p., 30 min before CRF). Pretreatment by metyrapone, the inhibitor of glucocorticoid synthesis was the most suitable approach because of a short-lasting inhibiting effect of the drug. Metyrapone pretreatment allowed us to prevent the acute corticosterone response to CRF and avoid the lasting effects of glucocorticoid deficiency. Intracerebroventricular injection of CRF caused fast increase in plasma corticosterone levels and significantly suppressed the occurrence of gastric erosion induced by indomethacin. Metyrapone administration prevented CRF-induced corticosterone rise and significantly attenuated the protective effect of CRF on the gastric mucosa against indomethacin-produced injury. The results suggest that CRF injected into the brain may induce protection against indomethacin-caused gastric injury through the participation of glucocorticoids.

[Mechanisms of analgesic action of corticotropin-releasing factor on somatic pain sensitivity in rats].

The article reviews our recent data on the mechanisms of corticotropin-releasing factor (CRF) effect on the somatic pain sensitivity. The involvement of opioid and glucocorticoid receptors and CRF receptors of type 2 in analgesic effect induced by systemic CRF was studied in rats. According to the data obtained CRF receptors of type 2 are involved in CRF-induced analgesia whereas CRF-induced analgesic effect may be manifested in opioid-dependent and opioid-independent forms that apparently depend on pain stimulus and anesthesia. Opioid-independent form of anaIgesia may be provided by glucocorticoids.

[A comparative analysis of corticosterone, cortisol and dexametasone effects on gastric erosion in rats].

We previously demonstrated that manifestation of gastroprotective or proulcerogenic effects of single dexamethasone injection depends on duration of the hormonal action before ulcerogenic stimulus, but not on the hormonal dose. In the present study we investigated dose and time dependence of corticosterone and cortisol effects on the gastric erosion in rats in comparative aspect with dexamethasone effects. Gastric erosion was induced by indomethacin (35 mg/kg, sc) in preliminary fasted rats. Single injection of corticosterone or cortisol at the doses of 25, 50, 100 mg/kg one hour before indomethacin administration resulted in dose dependent gastroprotective effects similar to dexamethasone effects. However, after extending the hormonal action till 24 h (before indomethacin administration), the gastroprotective effect of corticosterone (100 mg/kg) and cortisol (50 mg/kg) didn't transform into a proulcerogenic one, in contrast to dexamethasone, but simply disappeared. The absence of long-lasting corticosterone deficiency in blood after corticosterone and cortisol injection, which was observed after dexamethasone injection, could be at least one of the possible reasons for the absence of transformation of the gastroprotective action of corticosterone and cortisol to a proulcerogenic one.

[Gastroprotective action of corticotropin-releasing factor (CRF): involvement of glucocorticoids and CRF receptors type 2].

The stress response involves the activation of two corticotropin-releasing factor (CRF) receptors types 1 and 2. The pituitary type 1 CRF receptors represent the primary receptors to activate the hypothalamic-pituitary-adrenocortical axis and, consequently, glucocorticoid production. Exogenous CRF induces an increase in glucocorticoid production and may protect the gastric mucosa against stress-induced injury. Here we examined contribution of glucocorticoids and CRF receptors type 2 to gastroprotective effect of exogenous CRF. Gastric injury was induced by 3 him-mobilization (at 10 degrees C) in conscious rats or 3.5 h gastric ischemia-reperfusion in anaesthetized rats. Intraperitoneal administration of CRF at the doses of 1.25 or 2.5 Mg/kg increased plasma corticosterone levels and suppressed the occurrence of gastric erosion induced by each stimulus. Metyrapone injected before CRF caused an inhibition of CRF-induced corticosterone response and prevented the protective effect of CRF on the gastric mucosa against erosion caused by immobilization (at 10 degrees C). However, metyrapone injection did not influence the protective effect of CRF on the gastric mucosa against ischemia-reperfusion-induced lesion. The protective effect of CRF on the gastric mucosa against ischemia-reperfusion-induced lesion was prevented by the nonselective CRF receptor antagonist astressin and selective type 2 CRF receptor antagonist astressin2-B. The results obtained suggest that exogenous CRF may protect the gastric mucosa against injury through involvement of glucocorticoids and also through CRF receptors type 2.

[Role of glucocorticoids and capsaicin-sensitive neurons in gastroprotective effect of ischemic preconditioning].

The study was designed to investigate contribution of glucocorticoid hormones and capsaicin-sensitive neurons to gastroprotective effect of ischemic preconditioning against injury induced by 3.5 h gastric ischemia-reperfusion in rats. The contribution of glucocorticoids was investigated by an inhibition of corticosterone synthesis with metyrapone and adrenalectomy followed by corticosterone replacement. To estimate the role of capsaicin-sensitive neurons we used their desensitization. Gastric ischemia was performed by occlusion of celiac artery in anaesthetized rats. In the control animals gastric ischemic preconditioning (0.5 h ischemia-reperfusion) induced plasma corticosterone rise and attenuated gastric injury caused by 3.5 h ischemia-reperfusion. Both adrenalectomy and desensitization of capsaicin-sensitive neurons by itself aggravated ulcerogenic influence of 3.5 h gastric ischemia-reperfusion. However, only adrenalectomy or metyrapone pretreatment, but not desensitization ofcapsaicin-sensitive neurons prevented gastroprotective effect ofischemic preconditioning. The data suggest that glucocorticoids contribute to gastroprotective effect of ischemic preconditioning even in rats with desensitization of capsaicin-sensitive neurons. The findings support participation of capsaicin-sensitive neurons in gastroprotection against injury caused by prolonged ischemia-reperfusion, but not in gastroprotective effect ofischemic preconditioning.