Ludmila Filaretova

The hypothalamic–pituitary–adrenocortical system: Hormonal brain–gut interaction and gastroprotection

The hypothalamic-pituitary-adrenocortical system is a hormonal component of brain-gut axis. There are two opposite points of view regarding the influence of stress-induced activation of hypothalamic-pituitary-adrenocortical system on the stomach. According to the widely held view, glucocorticoids released during stress are ulcerogenic hormones and, therefore, stress-induced activation of hypothalamic-pituitary-adrenocortical system is harmful. The results of our investigations are, however, opposite to this traditional view. To estimate the action of glucocorticoids released during stress on the gastric mucosa, the effects of glucocorticoid deficiency or occupation of glucocorticoid receptors by the antagonist RU-38486 on the formation of stress-induced gastric erosions were estimated in rats. The reduction of stress-induced corticosterone release (induced by various experimental approaches) markedly potentiated a gastric erosion formation caused by stress and acute corticosterone replacement, mimicking stress-induced corticosterone response, prevented this erosion-potentiating effect. The administration of RU-38486 also caused a significant increase of vulnerability of gastric mucosa to stress action. Thus, an acute stress-induced increase of glucocorticoids has a gastroprotective action against stress-induced gastric injury. We also showed that various ulcerogenic stimuli, similar to stress, induce an increase in glucocorticoid production that in turn helps the gastric mucosa to resist against a harmful action of ulcerogenic stimuli. Gastroprotective action of glucocorticoids may be mediated by multiple actions, including maintenance of glucose homeostasis, gastric mucosal blood flow, mucus production and attenuation of enhanced gastric motility and microvascular permeability. For maintenance of gastric mucosal integrity glucocorticoids may cooperate with prostaglandins. In conclusion, these findings indicate that activation of hypothalamic-pituitary-adrenocortical system could be considered as a significant gastroprotective component of brain-gut axis.

Aggravation of nonsteroidal antiinflammatory drug gastropathy by glucocorticoid deficiency or blockade of glucocorticoid receptors in rats

Our previous investigations suggest that the reduction of stress-induced corticosterone release, or inhibition of corticosterone actions, promotes stress-induced gastric erosions in rats. In this study the effect of glucocorticoid deficiency on susceptibility to gastric mucosal injury by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated in rats. Gastric erosions induced in male rats by indomethacin (25 mg/kg sc) or acidified aspirin (40 mM po) were studied one week after adrenalectomy with or without corticosterone replacement or after occupation of glucocorticoid receptors by the antagonist RU-38486 during the period of erosion formation. Corticosterone for replacement (4 mg/kg sc) was injected 15 min before the administration of indomethacin or acidified aspirin to adrenalectomized rats. The antagonist RU-38486 (10 mg/kg po) was administered twice, 20 min before and 60 min after NSAID administration. Plasma corticosterone levels were measured by fluorometry. Gastric erosions were quantitated by measuring the area of damage. Indomethacin or acidified aspirin induced both plasma corticosterone rise and gastric erosions. Adrenalectomy decreased both basal and NSAID-induced corticosterone levels and markedly promoted gastric erosion formation caused by the NSAID. An acute corticosterone replacement mimicking indomethacin-and aspirin-induced corticosterone rise prevented the effect of adrenalectomy on the gastric erosions. The administration of the glucocorticoid/progesterone antagonist RU-38486 significantly potentiated the formation of gastric erosions induced by indomethacin as well as aspirin. These observations suggest a gastroprotective action of glucocorticoids released in response to NSAID treatment against NSAID-induced injury.

Mechanisms Underlying the Gastroprotective Action of Glucocorticoids Released in Response to Ulcerogenic Stress Factors

Abstract: 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.

Gastroprotective action of glucocorticoids during the formation and the healing of indomethacin-induced gastric erosions in rats

The aim of the present study consisted of the investigation of glucocorticoid role in the formation and the healing of indomethacin-induced (25 mg/kg, s.c.) gastric erosions in rats. The effect of deficiency of glucocorticoid production followed by corticosterone replacement on the formation and the healing of the gastric erosions was evaluated. Glucocorticoid production was decreased by adrenalectomy or by delayed inhibitory action after a single pharmacological dose of cortisol (300 mg/kg i.p.) injected 1 week before the onset of ulcerogenic stimulus. Indomethacin induced corticosterone rise and caused gastric erosions. The loss of indomethacin-induced plasma corticosterone rise potentiated the formation of indomethacin-induced erosions in both models. The area of gastric erosions in rats with glucocorticoid deficiency was considerably larger than that in control animals 4 h after indomethacin administration as well as during 48 h after the drug administration (period of erosion healing). Injecting corticosterone in rats with glucocorticoid deficiency significantly decreased the formation of indomethacin-induced gastric erosions and promoted their healing. Thus, the present data support the gastroprotective action of glucocorticoids in the formation and in the healing of indomethacin-induced mucosal injury.

Various ulcerogenic stimuli are potentiated by glucocorticoid deficiency in rats

The effects of glucocorticoid deficiency with or without corticosterone replacement on susceptibility to gastric mucosal injury by various ulcerogenic stimuli have been evaluated in rats. Gastric erosions were induced in male rats by stimuli of different modalities and intensities: 20% ethanol (po), aspirin (300 mg/kg, ip), acidified aspirin (40 mM, po) and 100% acetic acid (applied to gastric serosa). Glucocorticoid supply was decreased by adrenalectomy or by delayed inhibitory action after a single pharmacological dose of cortisol (300 mg/kg, ip) injected one week before the onset of ulcerogenic stimulus. Corticosterone for replacement (4 mg/kg, sc) was injected in rats with glucocorticoid deficiency 15 min before the onset of ulcerogenic stimulus. Plasma corticosterone levels were measured by fluorometry. Gastric erosions were quantitated by measuring the area of damage. Ulcerogenic stimuli induced both plasma corticosterone rise and gastric mucosal injury. The area of mucosal damages induced various stimuli ranged from small to extensive. Glucocorticoid deficiency significantly potentiated an ulcerogenic action of every ulcerogenic stimulus. Replacing corticosterone prevented or significantly decreased erosion-potentiating effect of glucocorticoid deficiency. These results show that endogenous glucocorticoids released during ulcerogenic influences help gastric mucosa to resist a harmful action of both weak and strong ulcerogenic stimuli.

Contribution of Glucocorticoids to Protective Influence of Preconditioning Mild Stress against Stress‐induced Gastric Erosions

It is known that preconditioning stress may attenuate stress‐induced gastric injury and that this effect is mediated by prostaglandins. In the present study we investigated the contribution of glucocorticoids to the gastroprotective effect of preconditioning stress. The effects of mild stress on gastric erosion caused by severe stress were compared in rats with normal and deficient corticosterone response to preconditioning mild stress. Mild stress decreased the gastric ulceration caused by severe stress, and this effect was prevented by glucocorticoid deficiency during mild stress. The results suggest that glucocorticoids released during preconditioning mild stress contribute to the gastroprotective effect of this stress.

Somatic pain sensitivity during formation and healing of acetic acid-induced gastric ulcers in conscious rats

A classical feature of visceral pain is its referring to somatic locations. Gastric ulcer is a source of visceral pain. In the present study we investigated whether gastric ulcers may trigger the changes in somatic nociception. For this aim somatic pain sensitivity was estimated under conditions of gastric ulcer development and healing. Gastric ulcers were induced by luminal application of 60% acetic acid under surgical conditions. Control rats were subjected to the same surgical procedure, but with the application of saline instead of the acid. Somatic pain sensitivity (tail flick latency), plasma corticosterone level, adrenal and thymus weight were investigated under conditions of the formation and the healing of gastric ulcers. The application of the acid resulted in the formation of kissing gastric ulcers, the increase of somatic pain sensitivity (the decrease of tail flick latency) as well as the appearance of typical signs of chronic stress: long-lasting increase of plasma corticosterone level, adrenal gland hypertrophy and thymus gland involution. Natural healing of gastric ulcers was accompanied by restoration of pain sensitivity as well as attenuation of the signs of chronic stress. Delay of ulcer healing by the daily indomethacin administration (2 mg/kg, s.c.) prevented the restoration of somatic pain sensitivity. The results suggest that chronic gastric ulcers may trigger somatic hypersensitivity.

Role of endogenous glucocorticoids in the healing of gastric erosions and chronic gastric ulcers in rats

To investigate the role of endogenous glucocorticoids in the healing of gastric lesions, we compared the healing of indomethacin- or cold-restraint-induced gastric erosions as well as aceticacid-induced ulcers in sham-operated rats, adrenalectomized rats and adrenalectomized rats with corticosterone replacement. Adrenalectomy was performed immediately after the formation of gastric erosions (4 h after indomethacin administration or 6 h after the onset of cold-restraint stress) or chronic ulcers (in 3 days after ingestion of acetic acid into the luminal side of the stomach). All ulcerogenic stimuli caused an increase in corticosterone production. Adrenalectomy created corticosterone deficiency and delayed the healing of gastric erosions and chronic ulcers. Replacing corticosterone reversed the deleterious effect of adrenalectomy on healing of gastric damage in adrenalectomized rats. These results suggest that glucocorticoids participate in natural healing processes of injured gastric mucosa. The data obtained also indicate that participation of glucocorticoid in the healing of gastric lesions is more evident under prostaglandin deficient conditions.

Stress in Physiological Studies

This review addresses the pioneering concepts of biological stress of Hans Selye, who demonstrated the key role of the hypophyseal-adrenocortical system in mediating the stress response. The review discusses the origins of the concept of stress and some aspects of contemporary physiological studies associated with activation of the hypothalamo-hypophyseal-adrenocortical system. The main focus is placed on results demonstrating that activation of the hypothalamo-hypophyseal-adrenocortical system provides the gastroprotective component of the stress response.

Analgesic Actions of Corticotropin-Releasing Factor (CRF) on Somatic Pain Sensitivity: Involvement of Glucocorticoid and CRF-2 Receptors

The aim of the present work was to study the involvement of glucocorticoid receptors and corticotropinreleasing factor type 2 receptors (CRF-2 receptors) in mediating the analgesic effects of CRF on somatic pain sensitivity. The involvement of glucocorticoid and CRF-2 receptors in the development of analgesia evoked by systemic administration of CRF was studied by blockade of these receptors by their specific antagonists RU 38486 and astressin 2-B, respectively, in anesthetized rats. Pain sensitivity was tested before and 30 min after administration of CRF in terms of the threshold of the pain reaction induced by stimulation of the rat’s tail with an electric current. Blockade of glucocorticoid receptors induced partial suppression of the analgesic action of CRF, while blockade of CRF-2 receptors produced complete suppression of the analgesic effect. These results provide evidence that glucocorticoid and CRF-2 receptors are involved in mediating the analgesic effects of CRF.