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.

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.

[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.

Central corticotropin-releasing factor (CRF) may attenuate somatic pain sensitivity through involvement of glucocorticoids.

Corticotropin-releasing factor (CRF) is an important regulator of physiological functions and behavior in stress. Analgesia is one of the characteristics of stress reaction and CRF is involved in providing stress-induced analgesia, however, the underlying mechanisms remain to be determined. Exogenous CRF mimics stress effects on pain sensitivity and causes analgesic effect. The present study was performed to investigate the participation of endogenous glucocorticoids in analgesic effects induced by central administration of CRF in anesthetized rats. The participation of glucocorticoids was studied by pharmacological suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis as well as an occupation of glucocorticoid receptors by its antagonist RU 38486. Since CRF administration causes the release of ß-endorphin from the pituitary, the opioid antagonist naltrexone was used to determine the contribution of opioid-dependent mechanism to CRF-induced analgesia. An electrical current threshold test was applied for measurement of somatic pain sensitivity in anesthetized rats. Intracerebroventricular administration of CRF (2 µg/rat) caused analgesic effects (an increase of pain thresholds) and an increase in plasma corticosterone levels. Pretreatment with naltrexone did not change analgesic effects of central CRF as well as corticosterone levels in blood plasma. However, pharmacological suppression of the HPA axis leading to an inability of corticosterone release in response to CRF resulted in an elimination of CRF-induced analgesic effects. Pretreatment with RU 38486 also resulted in an elimination of CRF-induced effects. The data suggest that CRF-induced analgesic effects may be mediated by nonopioid mechanism associated with endogenous glucocorticoids released in response to central CRF administration.

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.

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 corticotropin-releasing 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.

The role of hypothalamo-hypophyseal-adrenocortical system hormones in controlling pain sensitivity.

The present review addresses analysis of data demonstrating the role of the hypothalamo-hypophyseal-adrenocortical axis (HHACA) in controlling pain sensitivity. Experiments on rats have demonstrated the analgesic effects of exogenous hormones of all components of the HHACA - corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids - in the same models, and have also shown that the opioid and non-opioid mechanisms contribute to the development of the analgesia induced by these hormones. Endogenous glucocorticoids are involved in the development of analgesia mediated by non-opioid mechanisms. Along with the non-opioid mechanisms associated with endogenous glucocorticoids, the analgesic effect of ACTH can be mediated by the opioid mechanism. Unlike the situation with ACTH, the analgesic effect of CRH is mediated exclusively by non-opioid mechanisms, one of which is associated with HHACA hormones, while the other, appearing only on systemic administration, is not associated with these hormones. The actions of glucocorticoids on pain are mediated by neurons in the central gray matter of the midbrain.

The role of the hormones of the hypothalamo-hypophyseal-adrenocortical system in the analgesic effect of corticotropin-releasing hormone.

Experiments on anesthetized male rats were performed to study the role of the hormones of the hypothalamo-hypophyseal-adrenocortical system (HHACS) in analgesia induced by central or systemic administration of corticoliberin-releasing hormone (CRF). Studies of the contribution of HHACS hormones were performed by blocking HHACS function by administration of hydrocortisone at a pharmacological dose one week before experiments started. Blockade of HHACS function, resulting in the inability of the system to increase hormone levels, resulted in a decrease in the analgesic effect resulting from systemic administration of CRF and completely abolished the analgesic effect after central administration of CRF. These data lead to the conclusion that there are two components involved in increasing the pain sensitivity threshold in response to administration of CRF: 1) a component dependent on HHACS hormones in central and systemic administration of CRF; 2) a component independent of HHACS hormones on systemic administration of CRF.

Analgesic effect of corticotropin-releasing hormone: involvement of the hypothalamic-pituitary-adrenocortical axis into its realization.

Involvement of hypothalamic-pituitary-adrenocortical axis into the analgesic effect of corticotropin-releasing hormone after its systemic administration was studied in experiments on rats. Pharmacological blockade of the hypothalamic-pituitary-adrenocortical axis decreased the duration and degree of the analgesic effect of corticotropin-releasing hormone. This analgesic effect can be mediated via two pathways: related to hormones of the hypothalamic-pituitary-adrenocortical axis and independent of these hormones.

The role of adrenocorticotropic hormone in the inhibition of pain reactions in conscious rats.

Experiments on conscious male Sprague-Dawley rats were performed to study the effects of adrenocorticotropic hormone (ACTH) on pain reactions. Pain sensitivity was assessed in terms of the latent period of tail withdrawal in response to heat. Systemic administration of ACTH and glucocorticoids to animals with normal levels of hormone production led to increases in the latent period of the tailflick reaction. The roles of glucocorticoids and opioid peptides in ACTH-induced analgesia were addressed in experiment on animals with deficient glucocorticoid production and animals in which opiate receptors were blocked with naltrexone. Deficiency in glucocorticoid production had no effect on ACTH-induced increases in the latent period of the tailflick reaction, while blockade of opiate receptors completely eliminated this effect of ACTH. ACTH-induced analgesia in conscious rats is mediated by opiate receptors and not by glucocorticoids.

Mechanisms of the effects of adrenocorticotropic hormone on pain sensitivity in rats.

Experiments on anaesthetized male Sprague-Dawley rats were performed to study the effects of adrenocorticotropic hormone (ACTH) on pain sensitivity. Systemic administration of ACTH to animals with normal hormone production induced rapidly developing (starting at 3 min) and prolonged (30 min) increases in pain response thresholds. Blockade of opiate receptors led to suppression of the initial stage of the analgesic effect of ACTH: the response was seen only from 15 to 30 min. In animals with deficient glucocorticoid production, the duration of the analgesic action of ACTH decreased to 15 min. Analgesia was completely eliminated by the combination of suppression of glucocorticoid production and blockade of opiate receptors. The analgesic effect of ACTH was mediated by two mechanisms: 1) a rapidly-acting (from 3 to 15 min) mechanism associated with opiate receptors and not related to glucocorticoids, and 2) a delayed (from 15 to 30 min) mechanism associated with glucocorticoids but not opiate receptors.

Effect of ACTH on pain sensitivity in rats.

Systemic administration of ACTH to rats with normal hormone production induced a rapid (started 3 min postinjection) and long-term (persisted 30 min) elevation of pain threshold. Complete inhibition of glucocorticoid production shortened the duration of ACTH-induced analgesia to 15 min. The biphasic effect of ACTH on pain sensitivity is probably mediated by short-term glucocorticoid-independent and long-term glucocorticoid-dependent mechanisms.

Stress-induced analgesia. The role of hormones produced by the hypophyseal-adrenocortical system.

Experimental studies on the effects of stress on blood corticosteroid levels and the appearance of analgesia were carried out on rats anesthetized with Nembutai (4 mg/100 g). Stress, consisting of stimulation of the hind footpad with a current at 0.7 mA, produced parallel changes in plasma corticosteroid concentrations and the threshold of a pain response. Functional blockade of the hypophyseal-adrenocortical system, produced by systemic administration of hydrocortisone (15 mg/100 g) or by implantation of dexamethasone (200 micrograms) above the paraventricular nucleus of the hypothalamus, resulted in reductions in stress-induced analgesia. Dosage with naloxone (1 and 10 mg/kg) had no effect on the level of analgesia or corticosteroid concentrations. It is concluded that stress-induced analgesia not mediated by opioids is corticosteroid-dependent.

Corticosteroid feedback: II. Role of hypothalamus and hypophysis.

The role of the paraventricular nucleus (PVN) of the hypothalamus and the hypophysis in ensuring the corticosteroid feedback of the pituitary-adrenocortical system (PACS) in rats was characterized by administration of increasing doses of hydrocortisone. The doses 100, 300 and 1200 micrograms/100 g b.w. of hydrocortisone were administered intraperitoneally. The injection of hydrocortisone in the dose of 1200 micrograms/100 g b.w. reduces the pituitrin-induced rise of ACTH content in plasma. The reduction of pituitary reactivity to pituitrin was not observed with the injection of smaller doses of hydrocortisone. The involvement of the hypothalamus in ensuring the corticosteroid feedback was estimated by the suppression of the stress-induced PACS reaction in animals with bilateral PVN lesions. The inhibition of the stress-induced corticosteroid rise did not occur in animals with the PVN lesions if they were treated with hydrocortisone in the dose of 100 and 300 micrograms/100 g b.w. At the dose of 1200 micrograms/100 g b.w. the inhibition of the stress-induced reaction is observed but it is less pronounced as compared to the control. The conclusion is made that at small, close to physiological doses of hydrocortisone (100 and 300 micrograms/100 g b.w.) the PACS inhibition is ensured by PVN involvement into the feedback pathways. At supraphysiological doses of hydrocortisone (1200 micrograms/100 g b.w.) the inhibition of PACS reaction is performed due to not only the hypothalamic PVN but the reduction in the pituitary reactivity.