Biomedical subjects

M L Vargas

Publications and source records attributed to M L Vargas.

At least 19 recordsLinked to original sources

PubMed2001

Synergistic interaction of diazepam with 3',5'-cyclic adenosine monophosphate-elevating agents on rat aortic rings.

We investigated the effect of the phosphodiesterase type 4 (PDE4) inhibitory activity of diazepam on the arterial wall. To this purpose, we examined the interaction of diazepam with 3',5'-cyclic adenosine monophosphate (cyclic AMP)-elevating agents on vasodilatation and cyclic AMP levels in rat aortic rings precontracted with phenylephrine. The involvement of benzodiazepine receptors was also studied. Diazepam (5-100 microM) produced a relaxation of this preparation which was neither mimicked by gamma-aminobutyric acid (GABA), nor antagonized by flumazenil and 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195), inhibitors of central or peripheral type benzodiazepine receptors, respectively. The diazepam-induced relaxation was potentiated by the presence of isoprenaline (10 nM), forskolin (50 nM) or milrinone (0.1 microM). Furthermore, diazepam increased the enhancement of cyclic AMP levels induced by these three agents in this tissue. Our results demonstrate a functional and biochemical synergistic interaction of diazepam with cyclic AMP-elevating agents on rat aortic rings.

Animals↗

PubMed2001

Diazepam increases the hypothalamic-pituitary-adrenocortical (HPA) axis activity by a cyclic AMP-dependent mechanism.

1. Previous studies in this laboratory have shown that diazepam behaves as a phosphodiesterase 4 (PDE 4) inhibitor. It has been reported that PDE-4 inhibitors activate the hypothalamic-pituitary-adrenocortical (HPA) axis in the rat. In the present study we have examined whether activation of the cyclic AMP-dependent protein kinase (PKA) is involved in the effect of diazepam on basal HPA axis activity. 2. Acute systemic administration of diazepam (10 mg kg(-1) i.p.) was found to increase the basal HPA axis activity, increasing the plasma concentrations of corticotrophin (ACTH) and corticosterone 30 min post injection. Diazepam also elevated cyclic AMP content of the hypothalamus. 3. Pretreatment of the animals with dexamethasone (1 mg kg(-1) s.c.) for 3 days completely abolished the effect of diazepam on HPA axis activity. 4. The antagonists of central and peripheral benzodiazepine receptors, flumazenil (10 mg kg(-1) i.p.) and PK 11195 (5 mg kg(-1) i.p.) did not affect the diazepam induced increase of HPA axis activity nor did they have an effect per se. 5. The increase in ACTH and corticosterone levels was significantly reduced by the cyclic AMP-dependent protein kinase (PKA) inhibitor, H-89, given either subcutaneously (5 mg kg(-1) s.c.) or intracerebroventricularly (i.c.v.; 28 microg in 10 microl). 6. The results indicate that diazepam can stimulate basal HPA axis activity in the rat by a cyclic AMP-dependent PKA mediated pathway.

Adrenal Cortex↗

PubMed1997

Neurochemical activity of noradrenergic neurons and pituitary-adrenal response after naloxone-induced withdrawal: the role of calcium channels.

The influence of the L-type calcium channel antagonist nimodipine on both the activity of noradrenergic neurons projecting to the hypothalamus and the pituitary-adrenal response during morphine tolerance and withdrawal was analysed. Tissue concentration of hypothalamic noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxy-phenylethylen-glycol (MHPG) were determined by high-pressure liquid chromatography. Plasma corticosterone concentration (a marker of pituitary-adrenal activity) was measured by radioimmunoassay. Rats rendered tolerant to morphine decreased hypothalamic MHPG concentration, and reduced hypothalamic NA turnover. Chronic infusion of nimodipine concurrently with morphine prevented the decrease in NA turnover during tolerance. After naloxone administration to tolerant rats we found a striking parallelism between an increased activity of the hypothalamic-pituitary-adrenal axis and an enhanced activity of noradrenergic neurons projecting to the hypothalamus. However, hypothalamic NA turnover and MHPG concentration, both elevated during withdrawal, returned to control levels in rats infused chronically with nimodipine, concomitantly with a reduction of the secretion of corticosterone. Taken together, these data indicate that increased noradrenergic neuronal activity in the hypothalamic nerve terminals is associated with the neuroendocrine morphine withdrawal syndrome and suggest that an up-regulated calcium system might contribute to the activation of these neurons.

Adrenal Glands↗

PubMed1996

Chronic naloxone-induced supersensitivity affects neither tolerance to nor physical dependence on morphine at hypothalamus-pituitary-adrenocortical axis.

This study reports the endocrine effects of chronic mu-blockade induced by naloxone on morphine tolerance and withdrawal at hypothalamus-pituitary-adrenocortical (HPA) axis level. Naloxone (0.5 mg/kg/h) or vehicle (1 microliter/h) were infused s.c. to Sprague-Dawley rats via osmotic minipumps for 7 days, concomitantly with morphine or placebo pellets for 7-8 days. In opiate-naive rats, the mu-preferring opioid agonist morphine (30 mg/kg) increased plasma corticosterone in a partial but significant naloxone-reversible manner. In vehicle-perfused rats, chronic morphine treatment produced tolerance to its neuroendocrine effect, while the development of morphine tolerance was antagonized in the naloxone-treated group. An enhancement of plasma corticosterone levels after acute morphine (30 mg/kg) occurred 24 h after removal of chronic naloxone treatment in vehicle-perfused rats, as a functional index of supersensitivity to the neuroendocrine effects of the mu agonist. By contrast, 24 h after naloxone removal, rats implanted with morphine pellets were significantly less sensitive to acute morphine (tolerance) than its control-placebo group. Substantial elevation of plasma corticosterone, accompanied by motor and behavioural signs, was observed after acute naloxone injection (1 mg/kg) to tolerant rats 24 h after naloxone-pumps removal, which indicates withdrawal. No endocrine, motor or behavioural signs appeared in the naloxone group with pumps in place. These results indicated that morphine desensitizes mu-opioid receptors that were probably upregulated by chronic naloxone in presence of chronic agonist administration, and suggest that opioid tolerance/dependence as well as opioid supersensitivity simultaneously and independently can occur at mu-opioid receptors mediating HPA function.

Animals↗

PubMed1994

Catecholaminergic mediation of morphine-induced activation of pituitary-adrenocortical axis in the rat: implication of alpha- and beta-adrenoceptors.

The present study investigates the role of hypothalamic catecholamines in the effects of morphine on hypothalamo-pituitary-adrenocortical (HPA) axis. Acutely administered morphine (30 mg/kg i.p) increased plasma corticosterone and reduced the hypothalamic noradrenaline (NA) content but it did not change either the dopamine (DA) concentration or the ratio DOPAC/DA. After reserpine administration the hypothalamic contents of NA and DA were drastically reduced without changing plasma corticosterone concentrations. The increase in plasma corticosterone induced by morphine was significantly reduced by the pretreatment with reserpine. The alpha 1- and alpha 2-antagonists prazosin and yohimbine, respectively, significantly antagonized the effect of morphine on plasma corticosterone. The beta-antagonist propranolol also significantly attenuated the increase of corticosterone secretion induced by morphine. The results suggest that the action of the opiate on HPA axis activity may be dependent on stimulatory catecholaminergic systems which utilize alpha 1-, alpha 2- and beta-adrenoceptors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Involvement of kappa-opioid receptor mechanisms in the calcitonin-induced potentiation of opioid effects at the hypothalamus-pituitary-adrenocortical axis.

The present study was conducted to evaluate the influence of calcitonin on the neuroendocrine effects of both the mu-opioid receptor agonist, morphine, and the selective kappa-opioid receptor agonist, U-50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidynyl)cyclohexyl]benzeneacetamide methane sulphonate), at the hypothalamus-pituitary-adrenocortical axis in rats. Calcitonin given alone (2.5, 5 or 10 UI/kg i.p.) induced no changes or a slight reduction (20 UI/kg i.p.) in plasma corticosterone, 45 min after its administration. Morphine did not produce any modification in plasma corticosterone at doses of 3 or 10 mg/kg i.p., whereas it produced a significant increase in corticosterone secretion at doses of 20 or 30 mg/kg i.p., 30 min after its administration. Pretreatment with calcitonin (2.5 UI/kg i.p.) 15 min before morphine (3 or 10 mg/kg i.p.) did not modify the effect of the opioid on plasma corticosterone. U-50,488H (0.5, 1, 5 or 15 mg/kg i.p.) induced an increase in the release of corticosterone only at the higher dose, 30 min after injection. Significantly higher plasma corticosterone levels after U-50,488H administration at doses of 0.5, 1 or 5 mg/kg i.p. were observed when calcitonin was administered 15 min before the kappa-opioid receptor agonist. The enhanced responsiveness of the hypothalamus-pituitary-adrenocortical axis to U-50,488H (1 mg/kg i.p.) in animals pretreated with calcitonin, was completely blocked by the selective kappa-opioid receptor antagonist, nor-binaltorphimine, suggesting a role of kappa-opioid receptors in mediating the calcitonin-induced supersensitivity to U-50,488H.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1994

Effects of intracerebroventricular clonidine on the hypothalamic noradrenaline and plasma corticosterone levels of opiate naive rats and after naloxone-induced withdrawal.

The aim of this study was to determine whether hypothalamic noradrenergic neuronal activity contributes to the abstinence-induced hypersecretion of corticosterone during naloxone-induced withdrawal. With this purpose the effects of intracerebroventricular (i.c.v.) clonidine on hypothalamic noradrenaline (NA) and plasma corticosterone were studied in chronically placebo-treated rats (controls) and during naloxone-induced morphine withdrawal. In control rats, clonidine (10 micrograms) significantly increased plasma levels of corticosterone without changing the hypothalamic content of NA. Naloxone (1 mg/kg, s.c.) also increased plasma corticosterone levels and clonidine administered prior to naloxone, antagonized the effect of naloxone on plasma corticosterone. In chronically morphine-treated rats, naloxone treatment induced an increase in plasma corticosterone and reduced the hypothalamic NA content. Clonidine significantly prevented the reduction in the hypothalamic NA, without modifying plasma levels of corticosterone. The results show an interaction between opioid-receptors and alpha 2-adrenoceptors in the hypothalamus, and suggest that mechanisms other than hyperactivity of NA neurons contribute to the hypothalamus-pituitary-adrenocortical (HPA) axis hyperactivity during the opiate withdrawal.

Animals↗

PubMed1994

Modulation by catecholamine of hypothalamus-pituitary-adrenocortical (HPA) axis activity in morphine-tolerance and withdrawal.

1. Hypothalamic noradrenaline (NA), dopamine (DA) and plasma corticosterone concentrations were determined after acute morphine administration to both naive and morphine-tolerant rats and during naloxone-induced withdrawal. 2. Acutely administered morphine (30 mg/kg) significantly increased the plasma level of corticosterone and reduced the NA and DA content in the hypothalamus. Naloxone (1 mg/kg), administered before morphine, blocked the effect of the opiate on both plasma corticosterone and hypothalamic NA concentration. 3. In chronically morphine-treated rats, a challenge dose of morphine (30 mg/kg) neither modified the plasma corticosterone level nor the NA concentration, while DA content was significantly enhanced. 4. After naloxone-induced withdrawal, the hypothalamic content of NA was significantly reduced, simultaneously with an increase in plasma corticosterone, while DA content remained unchanged. 5. These results suggest that the hypothalamic noradrenergic neurons are mainly mainly implicated in the effect of acute morphine on the hypothalamus-pituitary-adrenocortical (HPA) axis and in the tolerance development to this effect. The results also suggest that a hyperactivity of noradrenergic pathways in the hypothalamus would be one of the physiologically relevant mechanisms mediating the neuroendocrine opiate withdrawal at the HPA level.

Animals↗

PubMed1994

Lack of involvement of delta-opioid receptor in mediating physical dependence at the hypothalamus-pituitary-adrenocortical (HPA) axis in the rat.

1. In previous studies, we have demonstrated that delta-opioid receptors are involved both in the acute control of hypothalamus-pituitary-adrenocortical (HPA) axis activity and in the development of neuroendocrine opioid tolerance. In the present work we studied whether central delta-opioid receptors play a role in the development of neuroendocrine physical dependence to opioids in the rat. 2. Intracerebroventricular (i.c.v.) administration of the delta-selective agonist DPDPE ([D-Pen2,D-Pen2]enkephalin) produced stimulation of HPA activity, as shown by an increase in corticosterone release. This effect was antagonized by i.c.v. co-administration of ICI 174,864, a selective delta-receptor antagonist, which provide direct evidence that the activation of the HPA axis produced by DPDPE is mediated by central delta-opioid receptor. 3. Chronic pretreatment with i.c.v. DPDPE resulted in tolerance to its neuroendocrine effect. Intracerebroventricular injection of ICI 174,864 to DPDPE-tolerant rats produced neither alteration in corticosterone release nor behaviour signs of dependence. 4. It was concluded that delta-opioid receptors do not play a role in the development of opioid neuroendocrine physical dependence at the HPA axis.

Animals↗

PubMed1993

L-type Ca2+ channel ligands modulate morphine effects on the hypothalamus-pituitary-adrenocortical axis in rats.

The role of the L-type Ca2+ channel in the acute effects of morphine on the hypothalamo-pituitary-adrenocortical (HPA) system was studied by administration of the Ca2+ channel agonist, BAY K 8644, and the antagonists, verapamil and nimodipine, to rats. Morphine (30 mg/kg i.p.) induced an increase in corticosterone secretion 30 min after injection, which was correlated with a simultaneous change in hypothalamic noradrenaline (NA) and dopamine (DA) contents. Pretreatment with verapamil (10 or 20 mg/kg i.p.) or nimodipine (5 mg/kg i.p.) antagonized the HPA activation induced by morphine, blocking both the decrease in hypothalamic NA levels and the elevation in plasma corticosterone induced by the opioid. BAY K 8644 (2 mg/kg i.p.) potentiated the effects of morphine, decreasing the hypothalamic NA content and increasing the release of corticosterone. The Ca2+ channel antagonist, nimodipine, given alone induced a slight reduction in hypothalamic NA content but did not modify plasma corticosterone levels. Verapamil given alone did not alter HPA activity. Instead, the Ca2+ agonist decreased the hypothalamic catecholamine content and increased plasma corticosterone levels. These results indicate that Ca2+ influx is necessary for the expression of opioid actions on the HPA system, and suggest that the Ca2+ flux in hypothalamic neurons is functionally linked to activation of opioid receptors.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1993

Expression of adhesion molecules by endothelial cells of early human decidua.

The expression of adhesion molecules by endothelial cells (EC) of early human decidua was studied with monoclonal antibodies and the immunoperoxidase technique. Although E-selectin, INCAM-110 and VCAM-1 were poorly detected on decidual EC, ICAM-1, P-selectin and DR antigens were highly expressed by these cells, some of which showed high endothelial venule-like morphology. Our results suggest that decidual EC are activated, and are probably involved in the active recruitment of leucocytes.

Cell Adhesion Molecules↗

PubMed1993

Expression of class II HLA molecules by endothelial cells of human decidua.

Many authors have documented a high level of expression of class II HLA molecules by decidua. Although macrophages appear to be responsible for this, we show in this article that endothelial cells (EC) of the venules and capillaries of human decidua also strongly express class II molecules, whereas EC of chorionic villi do not. We discuss this finding in the context of the maternal-fetal immune interaction.

Arterioles↗

PubMed1993

Simultaneous changes in hypothalamic catecholamine levels and plasma corticosterone concentration in the rat after acute morphine and during tolerance.

The effects of morphine on plasma corticosterone and hypothalamic noradrenaline (NA) and dopamine (DA) content were studied in naive and in morphine-tolerant rats. Acutely administered morphine (30 mg/kg i.p.) significantly increased the plasma levels of corticosterone and significantly reduced the hypothalamic NA and DA content. In chronically morphine-treated rats (subcutaneously implanted with pellets for 7 days), a challenge dose of morphine (30 mg/kg intraperitoneally (i.p.)) did not modify the plasma corticosterone levels and inhibited the morphine-induced decreases in hypothalamic NA and DA content. These results suggest that: (1) In naive rats, the morphine-induced activation of hypothalamus-pituitary-adrenocortical (HPA) axis is mediated by catecholaminergic neurons in the hypothalamus; (2) In tolerant rats morphine did not modify the plasma corticosterone concentrations, presumably by attenuating hypothalamic noradrenergic and dopaminergic activity. (3) Hypothalamic catecholamines have a role in regulating the HPA axis during morphine tolerance.

Animals↗

PubMed1993

Comparison of the proportions of leukocytes in early and term human decidua.

The percentages of cells expressing immune markers were determined with immunohistochemistry and flow cytometry in early and term human decidua. Although we found no variation in the proportion of cells of bone marrow origin (CD45+), the percentages of T cells and CD16+ lymphocytes were significantly higher in term decidua. On the contrary, CD56+ lymphocytes, the most abundant leukocyte type in early decidua, decreased at term. These variations may reflex the immunological adaptations of decidua during pregnancy.

Antigens, CD↗

PubMed1993

Chronic kappa opioid receptor antagonism produces supersensitivity to U-50,488H at the hypothalamo-pituitary-adrenocortical (HPA) axis level.

The present study was conducted to evaluate the influence of chronic kappa receptor blockade on the neuroendocrine effects of the selective kappa 1 opioid agonist U-50,488H, on the hypothalamo-pituitary-adrenocortical (HPA) axis. Male Sprague-Dawley rats were chronically treated with naloxone (3 mg kg-1 day-1 for 7 days) or distilled water by s.c. implantation of osmotic minipumps and the response of the HPA axis to U-50,488H or saline was assessed before and 24 h after pump removal. Chronic infusion of naloxone reduced body weight gain and blocked the increase in corticosterone secretion induced by U-50,488H, indicating occupation of kappa opioid receptors. Significantly higher plasma corticosterone levels after U-50,488H administration at doses of 5 or 15 mg/kg were observed 1 day after cessation of naloxone treatment compared with those in corresponding control rats. The enhanced responsiveness of the HPA axis to U-50,488H (15 mg/kg) was antagonized by norbinaltorphimine (5 mg/kg), suggesting a role for kappa receptors in mediating supersensitivity to the kappa agonist. The findings of the present study demonstrated that chronic blockade of the kappa receptor results in augmentation of kappa agonist-induced stimulation of the HPA axis activity (functional supersensitivity).

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1993

Chronic naloxone treatment induces supersensitivity to a mu but not to a kappa agonist at the hypothalamus-pituitary-adrenocortical axis level.

It has been demonstrated previously that chronic treatment with opioid antagonists enhances the potency of opioid agonists (supersensitivity) and produces an increase in brain opioid binding sites (up-regulation). The objective of the present study was to examine whether chronic blockade of mu-opioid receptors with naloxone would produce functional supersensitivity to the action of selective mu- and/or kappa-opioid agonists, within the hypothalamus-pituitary-adrenocortical axis. Naloxone (0.5 mg/kg/hr) was infused s.c. to Sprague-Dawley rats via osmotic minipumps for 7 days. The increase in plasma corticosterone produced by 30 mg/kg i.p. of morphine in control rats was shown to be significantly higher in naloxone-pretreated rats, 24 hr after pump removal. Furthermore, in naloxone-pretreated rats, 10 mg/kg i.p. of morphine significantly increased corticosterone levels 24 hr after naloxone was withdrawn, whereas in control rats the concentration of corticosterone increased first after the 30-mg/kg dose. No supersensitivity could be detected to the stimulating action on corticosterone release of U-50,488H (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidynyl)cyclohexyl]ben zeneacetamide methane sulfonate; 1 or 15 mg/kg i.p.), 1 day after cessation of naloxone treatment. These data suggest that chronic blockade of the mu receptor with naloxone may induce a functional supersensitivity to the effects of mu- but not to those of kappa-agonists on the hypothalamus-pituitary-adrenocortical axis.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1992

Effects of clonidine on pituitary-adrenocortical axis in morphine-tolerant rats and after naloxone-induced withdrawal.

The effects of systemically administered clonidine on pituitary-adrenocortical axis in morphine-tolerant rats and after naloxone-induced withdrawal were examined. In naive animals, clonidine (0.5 and 1 mg/kg s.c.) significantly increased plasma beta-endorphin-like immunoreactivity (beta-END-LI) and cortisol levels. This effect was significantly reduced in morphine-tolerant animals. Naloxone treatment induced an increase of plasma beta-END-LI and cortisol levels in morphine-tolerant animals. The increase in cortisol level after withdrawal was significantly reduced by clonidine. These results are consistent with an interaction between alpha 2-adrenoceptors and opioid systems in the control of pituitary-adrenocortical axis during morphine tolerance and withdrawal.

Animals↗

PubMed1991

Effects of acute and chronic administration of mu- and delta-opioid agonists on the hypothalamic-pituitary-adrenocortical (HPA) axis in the rat.

The control of hypothalamic-pituitary-adrenocortical (HPA) activity by opioids seems to involve stimulatory and inhibitory pathways. The purpose of the present study was to determine the acute and chronic effects of selective mu- and delta-opioid agonists, administered centrally (i.c.v.) on pituitary-adrenocortical activity in the rat. The mu-agonist DAGO ([D-Ala2,N-MePhe4,Gly-ol5]enkephalin; 0.75 nmol i.c.v.) and the delta-agonist DPDPE ([D-Pen2,5]enkephalin; 194 nmol i.c.v.) both stimulated corticosterone release when administered acutely. Chronic administration of DAGO and DPDPE resulted in the development of tolerance to their neuroendocrine effects. These data suggest that both mu- and delta-opioid receptors are involved in the regulation of HPA activity under physiological conditions and during opiate abuse.

Analgesics↗