[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.

[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.

[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.

[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 glucocorticoid receptor blockade on analgesic effect of corticotropin-releasing factor.

The role of glucocorticoid receptors in the analgesic effect of corticotropin-releasing factor in rats was studied after glucocorticoid receptor blockade with antagonist RU 38486. Glucocorticoid hormones can potentiate the analgesic effect of corticotropin-releasing factor or modulate the mechanisms of this effect, which depends on the type of painful stimulus.

High sensitivity of gastric mucosa to ulcerogenic effect of indomethacin in rats with diabetes.

One week after injection of streptozotocin (60 mg/kg intravenously), rats developed diabetes associated with a significant increase of gastric mucosa sensitivity to the ulcerogenic effect of indomethacin (35 mg/kg subcutaneously). Since potentiation of the ulcerogenic effect of indomethacin was observed only in rats subjected to fasting before drug injection, we hypothesize that this effect was caused by a drop of high glucose level in the blood after fasting.

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.

Activation of the hypothalamo-hypophyseal-adrenocortical system as an important gastroprotective component of the stress reaction.

This article presents an analysis of data providing evidence of the important contribution of the hypothalamo-hypophyseal-adrenocortical system (HHACS) to the processes maintaining the integrity of the gastric mucosa. According to these data, glucocorticoid hormones produced during stress-induced activation of the HHACS are gastroprotective hormones rather than ulcerogenic factors, as is widely believed. The gastroprotective influence of glucocorticoids has been demonstrated on exposure to ulcerogenic stimuli of different modalities. The gastroprotective action of glucocorticoid hormones is mediated via type II glucocorticoid receptors and may be associated with the maintenance of the blood glucose level, their calming effects on pathogenetic factors, and their favorable effects on protective factors for the gastric mucosa. Glucocorticoid hormones can compensate for the absence of the gastroprotective action of prostaglandins, nitric oxide, and capsaicin-sensitive neurons. The data lead to the conclusion that activation of the HHACS is an important gastroprotective component of the stress reaction.

[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.

[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.

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.

Mechanisms underlying the gastroprotective action of glucocorticoids released in response to ulcerogenic stress factors.

Our previous results demonstrate the gastroprotective but not ulcerogenic action of glucocorticoids released in response to ulcerogenic stress factors. The present study was undertaken to investigate the possible mechanisms underlying the gastroprotective action of glucocorticoids in rat stomachs. The effects of deficiency of glucocorticoid production, with or without corticosterone supplementation, on blood flow velocity in gastric microvessels, microvascular permeability, mucus production, motility as well as gastric lesions were studied 3 to 4 h after the onset of ulcerogenic stimuli: water-restraint stress or indomethacin administration. The contribution of glucocorticoids in the healing process of gastric injury was also evaluated. The deficiency in glucocorticoid production significantly potentiated the functional disorders induced by ulcerogenic stimuli, such as a decrease in blood flow velocity and mucus production and an increase in gastric motility and in microvascular permeability, which resulted in aggravation of the formation of gastric lesions as well as impairment of their healing. The changes observed were prevented by supplementation of corticosterone at a dose mimicking a stress-induced corticosterone rise. We conclude that a gastroprotective action of glucocorticoids may be provided by multiple actions, including maintenance of the gastric mucosal blood flow and mucus production, attenuation of the enhanced gastric motility and microvascular permeability as well as beneficial influences on healing processes.

Role of the paraventricular and ventromedial hypothalamic nuclear areas in the regulation of the pituitary-adrenocortical system.

The role of the paraventricular (PVN) and ventromedial (VMN) hypothalamic nuclei in the activation and inhibition of the pituitary-adrenocortical system was studied in chronic experiments on rabbits. The functioning of the pituitary-adrenocortical system was estimated by changes in blood corticosteroid levels. PVN and VMN lesions resulted in a reduction of the stress-induced corticosteroid rise. VMN lesions resulted in smaller changes of the stress-induced response than PVN lesions while combined VMN and PVN lesions did not cause a larger reduction of the stress-induced activation than lesions of either area. The data obtained confirm that the PVN and VMN are connected in series. Hydrocortisone (100 micrograms/kg) administered intravenously 5 min before immobilization inhibits the stress-induced corticosteroid rise in intact rabbits. PVN and VMN lesions result in a reduction of the hydrocortisone inhibitory effect, PVN lesions having a greater effect than VMN ones. The PVN is of greater importance in both the activation and the inhibition of the pituitary-adrenocortical system than the VMN.

[Role of the paraventricular and ventromedial nuclei of the hypothalamus in activating the hypophyseal-adrenocortical system]. / Znachenie paraventrikuliarnykh i ventromedial'nykh iader gipotalamusa v aktivatsii gipofizarno-adrenokortikal'noi sistemy.

Immobilization of rabbits resulted in the activation of the pituitary-adrenocortical system. 3--7 weeks after lesion of paraventricular and ventromedial nuclei corticosteroid response to immobilization was inhibited. The rise of plasma corticosteroid level elicited by immobilization after paraventricular nucleus lesion was much smaller than after ventromedial nucleus lesion. The plasma corticosteroid response to stress in the group with paraventricular nucleus lesion plus ventromedial nucleus lesion was not lower than after lesion of paraventricular nucleus alone.

[The dependence of the formation of stress stomach ulcers on the function of the hypothalamo-hypophyseal-adrenal cortical system]. / Zavisimost' obrazovaniia stressornykh iazv zheludka ot sostoianiia gipotalamo-gipofizarno-adrenokortikal'noi sistemy.

The effect of supraphysiological doses of corticosteroids on mucosal ulceration of stomach was studied in rats. Cortisol (30 mg/100 g) blocked the PACS. During the PACS block, ulcerogenic properties of stressor increased. This effect was reduced by subsequent corticosterone replacement therapy. The new concept of supraphysiological doses of corticosteroids effect is discussed. The stomach ulceration seems to result from the corticosteroid insufficiency.

[The effect of large doses of corticosteroids on stomach ulcer formation: a new hypothesis]. / Vliianie bol'shikh doz kortikosteroidov na iazvoobrazovanie zheludka: novaia gipoteza.

A new hypothesis is suggested according to which the ulcerogenic effect of large corticosteroid doses is regarded as a consequence of suppression of hypothalamo-pituitary-adrenocortical system (HPAS) function. On the 7-th day after the administration of a large hydrocortisone dose to rats the HPAS block was observed. The HPAS block increased the area of hemorrhagic damages of the stomach mucosa induced by a stress factor. Similar data on the ulcer formation were obtained when using intrahypothalamic administration of dexamethasone. The replacement therapy decreased the effect of HPAS block in both cases. The data show that the stomach ulcer formation after the administration of high corticosteroid doses occurs as a result of endogenous hormone production insufficiency.