Do Thanh Kiem

α2-Adrenoreceptor subtypes regulate ACTH and β-endorphin secretions during stress in the rat

The effect of different α2-adrenoreceptor subtype agonists and antagonists on adrenocorticotrop hormone (ACTH) and β-endorphin release induced by ether stress was examined. Ether inhalation-induced ACTH and β-endorphin increase was inhibited by ICV administration of 30 μg but not 1 and 10 μg clonidine (α2-adrenoreceptor agonist). ICV oxymetazoline (α2A-adrenoreceptor agonist; 1–10–30 μg) or the α1-agonist methoxamine (100 μg/rat) failed to inhibit the stress-induced rise. Pretreatment with the αl/α2B,C-antagonist prazosin (0.5 mg/kg, IP) prevented the effect of clonidine on the ether stress, while the α1/α2A-antagonist WB-4101 (0.5 mg/kg, IP) was unable to counteract the inhibitory effect of clonidine. Prazosin alone had no effect on the ether-induced plasma ACTH and β-endorphin elevation. These results suggest that noradrenaline in the central nervous system may inhibit the stress-induced hypothalamo-pituitary-axis and pituitary β-endorphin activation via α2B,C-adrenoceptor subtypes and prazosin may antagonize its effect on these receptors.

Adrenocorticotropin, Prolactin and Beta-Endorphin Stimulatory Actions of Alpha-2-Adrenoceptor Antagonists

We studied the effect of glucocorticoid pretreatment, mediobasal hypothalamus lesion (MBHL) and the interaction between clonidine and yohimbine in male Wistar rats to elucidate the sites and/or mechanisms of endocrine actions of alpha 2-antagonists. The pretreatment of 1 mg/kg s.c. dexamethasone for 4 days effectively prevented the stimulatory effect of alpha 2-antagonists yohimbine (5 mg/kg i.p.) and CH-38083 (1 mg/kg i.p.) on adrenocorticotropin (ACTH) secretion, while the action of these antagonists on prolactin (PRL) and beta-endorphin (beta E) remained unchanged. The central (i.c.v.) pretreatment of 5 micrograms/rat clonidine failed to antagonize the prolactin (PRL) and beta E releasing effect of yohimbine. However, it inhibited the yohimbine-induced ACTH secretion. MBHL resulted in a significant enhancement in basal plasma PRL and beta-endorphin (beta E) levels. But basal plasma ACTH levels have not been changed. Yohimbine failed to stimulate ACTH secretion in MBH-lesions rats, while PRL and beta E response to the yohimbine was maintained in these animals. This study confirms that the alpha 2-antagonists stimulate ACTH secretion by a corticosteroid-sensitive mechanism which is located centrally. In contrast, alpha 2-antagonists affect PRL and beta E secretion via a corticosteroid-insensitive mechanism located at the periphery, possible within the pituitary gland.

Prolactin release induced by opiate agonists, effect of glucocorticoid pretreatment in intact and adrenalectomized rats

Cortisol administered at a dose of 25 mg/kg 24 h before measurements decreased the prolactin secretion induced by intraventricularly given opioids (dynorphin, beta-endorphin, Met-enkephalin or D-Met-Pro-enkephalinamide). The effect of cortisol was depressed by actinomycin D pretreatment. The cortisol-induced inhibition of the action of morphine was facilitated in adrenalectomized animals; measuring the effects of increasing doses of cortisol a maximal inhibition was obtained at a dose of 5 mg/kg. The opioid-induced corticosterone secretion was not affected 24 h after a single administration of cortisol. The present results show that the cortisol-induced inhibition of opioid-induced prolactin secretion is dependent on protein synthesis and independent of changes in drug metabolism, and of the type of opiate receptor preferentially affected by the opiate agonists employed.

Diurnal Variation in Prolactin, Adrenocorticotropin and Corticosterone Release Induced by Opiate Agonists in Intact and Adrenalectomized Rats

Diurnal variations of the effectivity of beta-endorphin (beta-End), dynorphin (DYN), Met-enkephalin (Met-Enk), D-Met2-Pro5-enkephalinamide (D-Met-Pro-Enk) and morphine to induce prolactin (PRL) and adrenocorticotropin (ACTH)/corticosterone (CS) release in intact and adrenalectomized rats have been examined. The response to morphine (10 mg/kg s.c.), Met-Enk (200 micrograms/rat i.c.v.) and D-Met-Pro-Enk (0.5 microgram/rat i.c.v.) did not change with different times of the day, while that to beta-End (0.5 microgram/rat i.c.v.), DYN (1 microgram/rat i.c.v.) and U50-488H, a selective kappa agonist (10 mg/kg s.c.), showed a circadian rhythm in stimulating PRL release, with a higher increase in the afternoon (16.00-17.00 h) than in the morning (08.00-09.00 h). In adrenalectomized rats the loss of this circadian rhythm was shown. The CS release evoked by morphine, D-Met-Pro-Enk, Met-Enk and DYN was demonstrable only in the morning when the basal CS level was significantly lower than in the afternoon. The afternoon release of ACTH by morphine was higher than in the morning in adrenalectomized rats. beta-End and U50-488H were equally active in the morning and in the afternoon in increasing CS secretion. The present results suggest that the diurnal rhythm in the response of CS and PRL release to opioids is in relation with the glucocorticoid secretion.

The effect of systemically and locally administered steroids on VIP-like immunoreactive cells in the paraventricular nucleus of adrenalectomized rats

Seven days after adrenalectomy (ADX) the number of vasoactive intestinal peptide (VIP)- and corticotropin-releasing factor (CRF)-immunoreactive cells in the parvocellular part of the rat paraventricular nucleus (PVN) increased markedly. Dexamethasone in the drinking water (started immediately after ADX) or its local implantation around the hypothalamic PVN reduced the ADX-induced increase in the number of VIP- and CRF-like immunoreactive neurones. The present results suggest that PVN might be the site at which glucocorticoids inhibit the increase in VIP-positive cells after ADX.

Hypothalamic α2A-adrenoceptors stimulate growth hormone release in the rat

Abstract Oxymetazoline, the relatively selective α 2A -adrenoceptor agonist (with more than 60-fold selectivity over the α 2B -adrenoceptor subtype), was administered into the lateral ventricle (i.c.v.) of rats and plasma growth hormone (GH) levels were measured. Oxymetazoline was more potent to release GH after i.c.v. administration than was clonidine; 0.01 μg i.c.v. oxymetazoline already caused a significant release of GH, while at least 0.1 μg clonidine had to be administered to cause a similar response. The dose-response curve was of an inverted U shape since with 10 μg of oxymetazoline the plasma GH did not rise. When oxymetazoline was injected i.c.v. to rats with somatostatin fibres to the median eminence transected by an anterolateral cut in the hypothalamus there was a significant rise in plasma GH, suggesting that oxymetazoline stimulated GHRH rather than inhibited somatostatin release. Pretreatment with CH-38083 (7,8-(methylenedioxy)-14-α-hydroxy-alloberban HCl, selective for α 2 -adrenoceptors but not differentiating between α 2A and α 2B subtypes), prevented the plasma GH rise normally elicited by 1 μg i.c.v. oxymetazoline. The α 2A - and α 1 -selective adrenoceptor antagonist, WB-4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane hydrochloride), prevented the GH rise normally induced by oxymetazoline while prazosin, the α 2B - and α 1 -selective adrenoceptor antagonist, prolonged the elevation occurring in the control rats between 30 and 60 min after oxymetazoline injection. Since both prazosin and WB-4101 are α 1 -adrenoceptor antagonists but differ in their action on α 2A and α 2B subtypes as well as in their action on oxymetazoline-induced GH secretion, the antagonist studies suggest that oxymetazoline stimulates GH release through activation of α 2A -adrenoceptors stimulatory to GHRH release, and not by an action through α 2B - or α 2C - or α 1 -adrenoceptors. Since WB-4101 also antagonized clonidine action on GH release we also suggest that the major component may be the stimulation of the α 2A -adrenoceptors in the clonidine action on GH release.

Revaluation of the Role of Alpha2-Adrenoreceptors in Morphine-Stimulated Release of Growth Hormone

The relationship between opioidergic and alpha 2-adrenergic system in the regulation of GH secretion was studied using a novel alpha 2-antagonist, CH-38083, and chronic treatment with yohimbine or clonidine. In male Wistar rats morphine (3 mg/kg s.c.), and clonidine (31 micrograms/kg i.p.) induced a significant increase in plasma GH levels. The pretreatment with the alpha 2-antagonist yohimbine (1 and 3 mg/kg) effectively inhibited the GH releasing effect or morphine and clonidine. CH-38083 at the dose of 1 mg/kg did not interfere with the morphine-induced GH secretion, while it fully antagonized the GH-releasing effect of clonidine. Higher doses (3 and 5 mg/kg) of CH-38083 only partly inhibited GH secretion induced by morphine. In rats chronically treated with clonidine (2 micrograms/ml in the drinking water for 14 days) the GH response to an injection of clonidine was blocked, while the effect of morphine on the GH secretion remained unchanged. In long-term castrated rats the effect of clonidine (15, 31 and 250 micrograms/kg i.p.) on the GH secretion was significantly blunted, while the GH-releasing effect of morphine (1, 3 and 5 mg/kg s.c.) remained unchanged. The replacement of testosterone (10 mg/kg for 4 days) in castrates restored the effect of clonidine, whereas it decreased the stimulatory action of morphine on the GH secretion. In rats chronically treated with yohimbine (2 mg/kg i.p. 2-3 times daily for 14 days until sacrifice), the GH response to a high dose of clonidine (0.5 mg/kg i.p.) was blocked, while the effect of morphine (5 mg/kg s.c.) was significantly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dexamethasone implanted in different brain areas on the morphine-induced PRL, GH and ACTH/corticosterone secretion

We studied the effect of dexamethasone (DEX) implantation in male Wistar rats to elucidate the site of action of morphine-induced prolactin (PRL), growth hormone (GH), adrenocorticotropic hormone (ACTH) and corticosterone (B) secretion. DEX or cholesterol was implanted in the close vicinity of the paraventricular (PVN), or the arcuate nuclei (ARN) of the hypothalamus or into the hippocampus. Five days after implantation blood samples were taken 30 min after i.p. morphine by decapitation or through an indwelling cannula 15, 30, 60 min after i.v. injection. DEX implanted near the PVN resulted in a blockade of morphine-induced ACTH and B secretion. In contrast, GH response to morphine was enhanced, while that of PRL was unchanged. DEX implanted near the ARN significantly inhibited the PRL-releasing effect of morphine, but was without any influence on the PRL secretion induced by haloperidol. There was a partial reduction in the B response to morphine, and GH secretion was unchanged. Dorsal hippocampal implants were without any effect on the morphine-induced GH, PRL or B secretion. We suggest that the site of glucocorticoid inhibitory action in the hypothalamus is the PVN for the opiate-induced ACTH/B secretion, and the ARN for the morphine-induced PRL release. The enhanced GH response to morphine observed in DEX-PVN implanted rats might be due to a decreased somatostatin tone.

Diurnal alteration in opiate effects on the hypothalamo-pituitary-adrenal axis: changes in the mechanism of action

Opioid control of the hypothalamo-pituitary-adrenocortical axis has a characteristic circadian rhythm (Kiem, Kanyicska, Stark and Fekete, 1987). To elucidate the mechanisms leading to circadian alterations of opioid control of the hypothalamo-pituitary-adrenocortical axis, and to look for the receptor type at which the p.m. inhibitory action of opioids occurs, we examined the effect of morphine at different doses and the interaction between naloxone and morphine at different times of day in intact male Wistar rats. In the morning: morphine (10 and 30 mg/kg s.c.) significantly increased corticosterone secretion, while 3 mg/kg s.c. had no effect. Naloxone in a dose of 2.5 mg/kg i.p. significantly antagonized the corticosterone-releasing effect of morphine, suggesting that the secretion of corticosterone induced by morphine is mediated via mu-opioid receptors. In the afternoon: basal plasma corticosterone levels were higher than those in the morning, and morphine caused a significant corticosterone increase only at the dose of 30 mg/kg, and had no effect in the dose of 10 mg/kg. Morphine significantly decreased corticosterone levels in the dose of 3 mg/kg. This inhibitory action lasted approximately 3 h after morphine injection and was able to inhibit the circadian evening rise of corticosterone. The effect of morphine and the interaction between naloxone and morphine on prolactin secretion remained unchanged from a.m. to p.m.; naloxone (2.5 mg/kg i.p.) which inhibited the 30 mg/kg morphine-induced corticosterone rise in the morning failed to antagonize the 3 mg/kg morphine-induced decrease of corticosterone secretion in the afternoon. A high dose of naloxone (10 mg/kg i.p.) effectively prevented the 3 mg/kg morphine-induced p.m. inhibition of corticosterone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Do alpha-2 adrenoceptors modify coping strategies in rats ?

Previous research has shown that resident rats treated with α2 adrenoceptor blockers display a modified aggressive response towards intruding animals. In the present study we report data on the behavioral changes induced by α2 adrenoceptor blockers in intruder animals. In experiments 1 and 2 intruders smaller in body weight than the residents were treated with 0.0, 0.5, and 1.0 mg/kg CH-38083 and idazoxan, respectively; in experiment 3 weight matched intruders were injected with 1 mg/kg CH-38083 or idazoxan. The treatment of smaller intruders did not change the behavior of residents. In contrast, weight-matched intruders injected with α2 adrenoceptor blockers elicited increased aggression in residents. Social behaviors, exploration and offensive aggression showed insignificant variation in intruders. Defensive behaviors, in contrast, showed major changes: in experiments 1 and 2 a dose-dependent decrease in immobility and a dose-dependent increase in defensive upright was noticed. In experiment 3, high scores of defensive upright were apparent, precluding detection of drug-induced changes. However, when the last 5 min of the encounter were analysed separately, results similar to the first two experiments were observed. Significant negative correlations were found between immobility and defensive upright scores. The results suggest that α2 adrenoceptor blockers induce a shift from a passive (immobility) towards a more active (defensive upright) coping style. These and previous data show that α2 adrenoceptor blockers, other than yohimbine, seem to exert a behavior-activating effect in rats.