T. R. Bagaeva

Effects of maternal corticosterone and stress on behavioral and hormonal indices of formalin pain in male and female offspring of different ages

In previous studies, we showed for the first time that prenatal stress in rats produces long-term alterations of formalin-induced pain behavior that are dependent on age and sex, and we demonstrated an important role of the serotonergic system in mechanisms of prenatal stress (Butkevich, I.P. and Vershinina, E.A., 2001; Butkevich, I.P. and Vershinina, E.A., 2003; Butkevich, I.P., Mikhailenko, V.A., Vershinina, E.A., Khozhai, L.I., Grigorev, I.P., Otellin, V.A., 2005; Butkevich, I.P., Mikhailenko, V.A., Khozhai, L.I., Otellin, V.A., 2006). In the present study, we focus on the influence of the maternal corticosterone milieu and its role in the effects of stress during pregnancy on formalin-induced pain and the corticosterone response to it in male and female offspring of different ages. For this purpose, we used adrenalectomy (AD) in female rats 3-4 weeks before mating (as distinct from AD typically performed at the beginning of pregnancy). Since AD is considered a reliable method to treat hypercortisolism, researches on the effects of long-term AD in dams on the systems responsible for adaptive behavior in offspring are important (such studies are not described in the literature). The results demonstrate that the differences in the corticosterone response to injection of formalin and saline are obvious in 90-day-old (adult) female offspring but masked in 25-day-old ones. AD promoted the corticosterone response to formalin-induced pain but not to injection of saline in prenatally non-stressed female offspring of both ages. Prenatal stress canceled the differences in corticosterone response to injection of formalin and saline in 25-day-old offspring of AD dams and in adult offspring of sham-operated (SH) dams but caused similar differences in adult offspring of AD dams. Sex differences were found in basal corticosterone levels in AD prenatally stressed rats of both age groups, with a higher level in females, and in the corticosterone response to formalin-induced pain in the adult rats of all groups investigated, with higher corticosterone levels in females. In regard to pain behavior, AD induced significant changes in flexing+shaking in prenatally non-stressed adult offspring and canceled the differences in this behavior between non-stressed and stressed 25-day-old offspring. There were sex differences in pain behavior of the adult rats: greater flexing+shaking in AD non-stressed males but in SH non-stressed females; greater licking in prenatally-stressed AD and SH females. These results indicate that the long-term influences of maternal corticosterone on formalin-induced pain and the corticosterone response to it are determined by the sex and age of the offspring and suggest that other mechanisms, including serotonergic ones revealed in our previous studies, are involved in the effects of prenatal stress on inflammatory pain behavior.

Mechanisms of the Analgesic Effect of Corticotropin-Releasing Factor in Conscious Rats

We report here our studies of the contribution of the hypothalamo-hypophyseal-adrenocortical system (HHACS) and opioid system to the analgesic effect of corticotropin-releasing factor (CRF) in conscious rats exposed to thermal stimuli. Two methodological approaches were used: 1) blockade of the functional activity of the HHACS by administration of hydrocortisone at a pharmacological dose one week before experiments; 2) blockade of glucocorticoid receptors with the glucocorticoid receptor antagonist RU38486. The contribution of the opioid system was studied by blockade of opioid receptors with their antagonist naltrexone. Blockade of opioid receptors completely eliminated the analgesic effect of CRF, blockade of the functional activity of the HHACS decreased it, and blockade of glucocorticoid receptors increased the effect. These data provide evidence that the analgesic effect of CRF in conscious rats exposed to a thermal stimulus is mediated by an opioid-associated mechanism. The actions of opioids on pain sensitivity may be modulated by glucocorticoid hormones.

Inflammatory Pain and Corticosterone Response in Infant Rats: Effect of 5-HT1A Agonist Buspirone Prior to Gestational Stress

Our researches have shown that gestational stress causes exacerbation of inflammatory pain in the offspring; the maternal 5-HT1A agonist buspirone before the stress prevents the adverse effect. The serotonergic system and hypothalamo-pituitary-adrenal (HPA) axis are closely interrelated. However, interrelations between inflammatory pain and the HPA axis during the hyporeactive period of the latter have not been studied. The present research demonstrates that formalin-induced pain causes a gradual and prolonged increase in plasma corticosterone level in 7-day-old male rats; twenty-four hours after injection of formalin, the basal corticosterone level still exceeds the initial basal corticosterone value. Chronic treatments of rat dams with buspirone before restraint stress during gestation normalize in the offspring pain-like behavior and induce during the acute phase in the formalin test the stronger corticosterone increase as compared to the stress hormonal elevation in animals with other prenatal treatments. Negative correlation between plasma corticosterone level and the number of flexes+shakes is revealed in buspirone+stress rats. The new data enhance the idea about relativity of the HPA axis hyporeactive period and suggest that maternal buspirone prior to stress during gestation may enhance an adaptive mechanism of the inflammatory nociceptive system in the infant male offspring through activation of the HPA axis peripheral link.

Early and Delayed Effects of Hypoxia during the Infantile Period on Behavioral and Hormonal Reactions of Rats

We studied the early and delayed effects of hypoxia during the infantile period on the behavioral reactions and corticosterone concentration in male rats. The elevation of corticosterone concentration, decrease in the immobility time (forced swimming test), and increase in the nociceptive response (formalin test) were observed in 7-day-old rats immediately after hypoxia. Adult animals exposed to hypoxia at the age of 7 days exhibited elevated basal corticosterone level and lengthened immobility time. Hypoxia had the same effect on plasma corticosterone concentration in 7-day-old and adult rats. Changes in corticosterone concentration after forced swimming were shown to differ in hypoxic animals and non-hypoxic specimens. Studying the dynamics of age-related variations in the test parameters will contribute to the understanding of pathogenetic mechanisms and development of new methods for pharmacological correction of postnatal changes in CNS after hypoxia during early ontogeny.

Persistent pain responses in inflammation and corticosterone levels in juvenile rats born to adrenalectomized dams

Studies in juvenile (Wistar) rats born to adrenalectomized dams (surgery performed 3–4 weeks before mating) addressed the intensity of behavioral pain responses (numbers of flexion + shaking patterns and durations of licking patterns) induced by foci of inflammation in the formalin test and plasma corticosterone levels on the background of the pain response. Maternal adrenalectomy had no effect on basal corticosterone levels or measures of the intensity of the pain response. In conditions of persistent pain (25 min after injection of formalin), corticosterone levels significantly (p < 0.05) increased in the offspring of both intact and operated dams. Females born to adrenalectomized dams, as compared with females from shamoperated dams, showed higher (p = 0.008) hormone levels in response to persistent pain. There were no differences in measures of the pain responses of the female offspring of adrenalectomized and sham-operated dams. There were no gender differences in measures of the pain response and hormone levels. Thus, pain evoked by acute foci of inflammation in the formalin test activated the hypothalamo-hypophysealadrenal system in 25-day-old rats, though the corticosterone released did not decrease pain intensity, which is consistent with data obtained from the offspring of adrenalectomized dams.

Mechanisms of the Analgesic Action of Corticotrophin-Releasing Factor on Somatic Pain Sensitivity in Rats

This review provides an analysis of data on the mechanisms of the analgesic action of corticotropin-releasing factor (CRF) on somatic pain sensitivity. Experiments on rats addressed the involvement of opioid and glucocorticoid receptors and type 2 CRF receptors in mediating the analgesic effect induced by systemic administration of CRF. The results showed that the analgesic action of CRF may involve type 2 CRF receptors; CRF analgesia can appear in two forms: opioid-dependent and opioid-independent, whose development appears to be determined by the nature of the pain stimulus and the use of anesthesia. The opioid-dependent form of analgesia may be supported by glucocorticoid hormones.

The Analgesic Effect of Corticotropin-Releasing Factor Given into the Periaqueductal Gray Matter of the Midbrain

Corticotropin-releasing factor (CRF) is involved in regulating stress-induced analgesia. One of the key structures of the brains antinociceptive system is the periaqueductal gray matter of the midbrain (PAGM). The aim of the present work was to study the effects of CRF given into the PAGM on pain sensitivity in conscious rats and the contribution of opioid mechanisms to mediating these effects. Somatic pain sensitivity was tested in terms of the latent period of the tail flick reaction in rats in response to thermal stimulation of the tail. The contribution of opioid mechanisms was studied by blockade of opioid receptors with the antagonist naltrexone, given both systemically and centrally into the PAGM. Administration of CRF (0.7 μg/rat into the PAGM induced an analgesic effect. Both systemic and central administration of naltrexone led to elimination of the analgesic effect of CRF, more quickly after central administration. The data obtained here provide evidence that one of the central mechanisms of the analgesic action of CRF on somatic pain sensitivity may be mediated by PAGM neurons with the involvement of opioid mechanisms.

Tonic Pain Response during Inflammation and Stress-Induced Corticosterone Variations in Prenatally Stressed Infant Rats: Effects of Maternal Buspirone Injected during Pregnancy

We studied the effects of injections of 5-HT1A-agonist buspirone to pregnant rats before stress exposure on corticosterone level in the dynamics of stress response to inflammatory-induced pain in 7-day-old offspring. During the period of the hypothalamic–pituitary–adrenal system hyporeactivity, the pain response in the formalin test was associated with stress-related corticosterone variations. Maternal buspirone normalized the pain reaction in prenatally stressed rats during all periods of the formalin test and modified the dynamics of the corticosterone response. In 1 day after the formalin test, the basal level of this hormone in blood plasma remained increased. Maternal buspirone increased the resistance of the nociceptive and stresssystems to inflammatory-induced pain response in prenatally stressed rats.

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.

Suppression of Hypothalamo-Hypophyseal-Adrenocortical System Function as the Cause of Aggravation of the Ulcerogenic Action of Indomethacin on the Stomach after Administration of Pharmacological Doses of Hydrocortisone

We report testing of the suggestion that aggravation of the actions of glucocorticoid treatment on the formation of indomethacin-induced erosions may be mediated by inadequate production of glucocorticoid hormones resulting from the suppression of the hypothalamo-hypophyseal-adrenocortical system (HHACS) in these conditions. Administration of indomethacin (25 mg/kg, s.c.) to rats after 24 h of starvation was used to induce gastric erosions. The effects of hydrocortisone given at pharmacological doses on the indomethacin-induced formation of gastric erosions and plasma corticosterone levels were studied one and four weeks after hormone administration. Indomethacin induced increases in plasma corticosterone levels, which were almost completely prevented one week after hydrocortisone administration. The formation of indomethacin-induced erosions was aggravated one week after administration of hydrocortisone, though replacement therapy with corticosterone, which imitates the normal increase in corticosterone, prevented this aggravation. Return of both the increased corticosterone level and the normal sensitivity of the gastric mucosa to the ulcerogenic action of indomethacin occurred four weeks after hydrocortisone administration. These results provide evidence that suppression of HHACS function may be responsible for the aggravation of the action of glucocorticoid treatment on the formation of erosions after administration of indomethacin.