Biomedical subjects

M L Laorden

Publications and source records attributed to M L Laorden.

At least 19 recordsLinked to original sources

PubMed2003

Effects of rolipram, pimobendan and zaprinast on ischaemia-induced dysrhythmias and on ventricular cyclic nucleotide content in the anaesthetized rat.

BACKGROUND AND OBJECTIVE: This study was designed to compare the haemodynamic, electrophysiological and pharmacodynamic effects of three selective inhibitors of the different isoenzyme forms of phosphodiesterase (PDE) on ischaemia-induced dysrhythmias in the anaesthetized rat. The drugs used were pimobendan, a selective PDE III inhibitor, rolipram, a selective PDE IV inhibitor, and zaprinast, a selective PDE V inhibitor. METHODS: The coronary artery was occluded 15 min after commencing drug administration, and myocardial ischaemia was maintained for 30 min during which the heart rate and mean arterial pressure were recorded. cAMP and cGMP were determined by radioimmunoassay. RESULTS: Pretreatment with rolipram decreased the duration of ventricular tachycardia without any change in the incidences of dysrhythmias or the mortality rate. This drug did not modify ventricular content of adenosine 3',5'-cyclic monophosphate (cAMP) or guanosine 3',5'-cyclic monophosphate (cGMP). Pimobendan (1 mg kg(-1) + 0.1 mg kg(-1) min) decreased the duration of ventricular tachycardia. This dose of pimobendan and zaprinast (1 mg kg(-1) + 0.1 mg kg(-1) min(-1)) increased the incidence rate of ventricular fibrillation following coronary artery ligation and the mortality rate. Moreover, both drugs increased cGMP in the ventricle. CONCLUSIONS: The results demonstrated that pimobendan and zaprinast increased the incidence of dysrhythmias and the mortality rate, which was accompanied by an increase in the ventricular content of cGMP. Rolipram decreased the duration of ventricular tachycardia without a change in the cyclic nucleotide content or in the mortality rate.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2003

Quantitative analysis of corticotropin-releasing factor and arginine vasopressin mRNA in the hypothalamus during chronic morphine treatment in rats: an in situ hybridization study.

The content of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) in the hypothalamic paraventricular nucleus (PVN) increases during chronic morphine treatment. Because these experiments cannot distinguish between increased synthesis or reduced release, the present study measured changes in CRF and AVP mRNAs in the PVN by in situ hybridization. Concomitantly, changes in noradrenaline turnover in the PVN and changes in plasma corticosterone release were determined. Male rats were implanted with placebo (naive) or morphine pellets for 7 days. On day 7, groups of rats received an acute injection of either saline i.p. or morphine (30 mg/kg, i.p.). Acute morphine injection did not change the total size of the labelled area for CRF mRNA in the PVN of naive or morphine-pelleted rats, indicating that the number of CRF-containing neurones was unchanged. On the other hand, in rats chronically treated with morphine, the intensity of labelling for CRF mRNA was significantly reduced, suggesting a decrease in the synthesis of CRF. In placebo rats, injection of saline or morphine did not affect the surface hybridized for AVP mRNA. By contrast, in the morphine-group injected with saline, there was a significant reduction in the number of labelled neurones, measured by the size of labelled area. Similarly, there was a decrease in intensity of AVP mRNA expression in the parvocellular and magnocellular neurones of the PVN in the morphine-group injected with saline, suggesting a decreased synthesis of AVP in these neurones. In parallel with the decrease in the expression of CRF and AVP mRNAs in the PVN, there was a pronounced decrease in noradrenaline turnover and in the release of corticosterone in the morphine-pelleted rats. In conclusion, present results show that, in addition to modifications in corticosterone secretion and in noradrenaline turnover, chronic morphine administration produces a reduction in the synthesis of CRF and AVP.

Animals↗

PubMed2002

Effect of naloxone-precipitated morphine withdrawal on CRH and vasopressin mRNA expression in the rat hypothalamic paraventricular nucleus.

Morphine withdrawal is characterized by an increase in the hypothalamus-pituitary-adrenocortical (HPA) axis activity. Here, by means of in situ hybridization, the changes in CRH and vasopressin (AVP) mRNAs have been analysed within the rat hypothalamic paraventricular nucleus (PVN) during morphine dependence and after naloxone-precipitated morphine withdrawal. CRH and AVP mRNA expression were analysed 30 min following administration of saline or naloxone to control groups and to morphine dependent rats. The data for in situ hybridization analysis of PVN neurons show that there were no changes in the total size of labelled area for CRH or AVP mRNA during morphine withdrawal, indicating that dependence on morphine does not involve alterations in the number of neurons expressing CRH or AVP mRNA. However, levels of mRNA encoding for CRH were decreased in the PVN during morphine dependence and withdrawal. By contrast, injection of saline or naloxone to morphine dependent rats did not affect the intensity of AVM mRNA expression. All these findings are discussed in term of cellular events that couple morphine dependence-increased HPA axis activity with changes in gene expression in selective neurons of the PVN.

Adrenocorticotropic Hormone↗

PubMed2001

Characterization of the signal transduction pathways mediating morphine withdrawal-stimulated c-fos expression in hypothalamic nuclei.

The transcription factor, Fos, is considered as a functional marker of activated neurons. We have shown previously that acute administration of morphine induces the expression of Fos in hypothalamic nuclei associated with control of the hypothalamus-pituitary-adrenocortex axis, such as the paraventricular nucleus and the supraoptic nucleus. In the current study, we examined the role of protein kinase A, protein kinase C and Ca2+ entry through L-type Ca2+ channels in naloxone-precipitated Fos expression in the paraventricular and supraoptic nuclei. After 7 days of morphine treatment, we did not observe any modification in Fos production. However, when opioid withdrawal was precipitated with naloxone a dramatic increase in Fos immunoreactivity was observed in the parvocellular division of the paraventricular nucleus and in the supraoptic nucleus. Chronic co-administration of chelerythrine (a selective protein kinase C inhibitor acting at its catalytic domain) with morphine did not affect the increase in Fos expression observed in nuclei from morphine withdrawn rats. In addition, infusion of calphostin C (another protein kinase C inhibitor, which interacts with its regulatory domain) did not modify the morphine withdrawal-induced expression of Fos. In contrast, when the selective protein kinase A inhibitor, N-(2'guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004), was infused it greatly diminished the increased Fos production observed in morphine-withdrawn rats. Furthermore, chronic infusion of the selective L-type Ca2+ channel antagonist, nimodipine, significantly inhibited the enhancement of Fos induction in the paraventricular and supraoptic nuclei from morphine-withdrawn animals. Taken together, these data might indicate that protein kinase A activity is necessary for the expression of Fos during morphine withdrawal and that an up-regulated Ca2+ system might contribute to the activation of Fos. The present findings suggest that protein kinase A and Ca2+ influx through L-type Ca2+ channels might contribute to the activation of neuroendocrine cells in the paraventricular and supraoptic nuclei.

Animals↗

PubMed2001

Combined phosphodiesterase inhibition and beta-blockade in the GI104313, decreases ischemia-induced arrhythmias in the rat.

PURPOSE: The purpose of the present study was to evaluate the effects of GI104313, a chimeric molecule containing a phosphodiesterase inhibiting pyradazinone and a blocking phenoxpropanolamine, on ischemia-induced arrhythmias in anesthetized rats. METHOD: The coronary artery was occluded 15 min after commencing drug administration and myocardial ischemia was maintained for 30 min during which the heart rate and mean blood pressure were recorded. Cyclic AMP and GMP were determined by radio-immunoassay. RESULTS: GI104313 (0.1 micromol x kg(-1) plus 0.01 micromol x kg(-1) x min(-1) or 1 micromol x kg(-1) plus 0.1 micromol x kg(-1) x min(-1)) decreased the incidence of ventricular tachycardia (86% and 75%), ventricular fibrillation (28%, P <0.01 and 12%, P <0.001) and premature ventricular beats (164 +/- 27.0 and 114 +/- 28.5, P <0.05) following coronary artery ligation, resulting in a decrease in mortality (29% and 12%, P <0.05). Changes in cyclic nucleotide concentrations have been implicated in the genesis of ischemia-induced arrhythmias. However, in the present study GI104313 did not change the concentrations of adenosine 3':5'-cyclic monophosphate (cyclic AMP) (1.0 +/- 0.07 pmol x mg(-1), 1.0 +/- 0.05 pmol x mg(-1)) or guanosine 3':5'-cyclic monophosphate (cyclic GMP) (0.025 +/- 0.008 pmol x mg(-1) protein, 0.017 +/- 0.004 pmol x mg(-1) protein) in the left ventricle during ischemia-induced arrhythmias in anesthetized rats compared to saline (0.9 +/- 0.1 pmol x mg(-1) and 0.013 +/- 0.002 pmol x m(-1), respectively). CONCLUSION: Our results demonstrate that, in rats, GI104313 induced a decrease in both incidence of arrhythmias and mortality which was not associated with changes in ventricular cyclic nucleotide content.

Adrenergic beta-Antagonists↗

PubMed2001

Evidence for a peripheral mechanism in cardiac opioid withdrawal.

Studies involving heart catecholaminergic systems in morphine-dependent rats have not established whether the adaptive changes observed in the heart during morphine withdrawal are mediated peripherally or centrally. In this study, naloxone (Nx), naloxone methiodide (NxM) and N-methyl levallorphan (NML), quaternary derivatives of Nx and levallorphan, respectively, that do not cross the blood-brain barrier, were administered to morphine-dependent rats and catecholamines and their metabolites determined in the right ventricle. Rats were made dependent on morphine by implantation of morphine pellets for 7 days. On day 8 animals received s.c. injections of saline, Nx (1 mg/kg), NxM (5 mg/kg) or NML (5 mg/kg) and were decapitated 30 min later. Noradrenaline (NA) and its metabolites normetanephrine (NMN) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined by high-performance liquid chromatography with electrochemical detection. After NxM or NML administration to morphine-dependent rats there was a pronounced increase in NMN and DOPAC levels, as well as in NA and DA turnovers (as estimated by NMN/NA and DOPAC/DA ratios, respectively) in the right ventricle. Similarly, giving Nx to morphine-dependent rats increased NMN and DOPAC levels and NA and DA turnovers. In addition, in the paraventricular nucleus of the hypothalamus (PVN) NA and DA turnover, measured as the MHPG/NA or DOPAC/DA ratios, increased after Nx administration but not after NxM or NML These results suggest that the changes in cardiac sympathetic activity observed during morphine withdrawal are due to intrinsic mechanisms outside the central nervous system. These data may be important for understanding the adaptive changes induced in the heart in subjects dependent on opioids.

Animals↗

PubMed2001

Effects of morphine withdrawal on catecholaminergic neurons on heart right ventricle; implication of dopamine receptors.

The purpose of our study was to examine the effects of D1-and D2-dopamine receptors blockade on the changes in the ventricular content of catecholamines in rats withdrawn from morphine. Rats were given morphine by subcutaneous (s.c.) implantation of morphine pellets for 5 days. On the eighth day, morphine withdrawal was induced by s.c. administration of naloxone (1 mg/kg), and rats were killed 30 min later. Pretreatment with SCH 23390 (dopamine D1, D5 receptor antagonist) 15 min prior to naloxone administration suppressed some the behavioural signs of morphine withdrawal, whereas eticlopride (dopamine D2, D3, D4 receptor antagonist) did not. In addition, biochemical analysis indicate that SCH 23390 completely abolished the withdrawal-induced increase in noradrenaline and dopamine turnover in the right ventricle. By contrast, eticlopride did not block the hyperactivity of catecholaminergic neurons in the heart during morphine withdrawal. These data suggest that the hyperactivity of catecholaminergic neurons in the heart during morphine withdrawal is dependent upon D1 dopamine receptor activation. In addition, our results exclude the involvement of D2 dopamine receptors.

Analgesics, Opioid↗

PubMed2000

Changes in catecholaminergic pathways innervating the rat heart ventricle during morphine dependence. Involvement Of alpha(1)- and alpha(2)-adrenoceptors.

In the present study, we examined the effects of alpha(1)- and the alpha(2)-adrenoceptors blockade on the changes in the ventricular content of catecholamines in rats withdrawn from morphine. Rats were given morphine by s.c. implantation of morphine pellets for 5 days. On the seventh day, morphine withdrawal was induced by s.c. administration of naloxone (1 mg/kg), and rats were killed 30 min later. Pretreatment with yohimbine (alpha(2)-adrenoceptor) or prazosin (alpha(1)-adrenoceptor) 15 min prior to naloxone administration attenuated some of the behavioural signs of morphine withdrawal. In addition, biochemical analysis indicated that yohimbine completely abolished the withdrawal-induced increase in noradrenaline and dopamine turnover in the right ventricle. By contrast, prazosin did not block the hyperactivity of catecholaminergic neurons in the heart during withdrawal. These data suggest that the hyperactivity of catecholaminergic neurons in the heart during morphine withdrawal is dependent upon alpha(2)-adrenoceptor activation. In addition, the present results rule out the involvement of alpha(1)-adrenoceptors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Changes in hypothalamic paraventricular nucleus catecholaminergic activity after acute and chronic morphine administration.

The participation of hypothalamic noradrenaline in the expression of neuroendocrine signs of morphine withdrawal has been proposed. The present study in rats examined: (1) the relationships between corticosterone secretion and the possible modifications in noradrenaline and dopamine content and turnover in the hypothalamic paraventricular nucleus after acute and chronic morphine administration; (2) the changes in cyclic adenosine monophosphate (cAMP) levels in the paraventricular nucleus after the same treatments. The results showed that acute morphine injection in control rats increased corticosterone release, 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) production, and noradrenaline turnover. Dopamine turnover in the paraventricular nucleus was decreased and the cAMP levels remained unchanged. In chronic morphine-treated rats, there was no elevation in noradrenaline turnover or in corticosterone secretion, indicating that tolerance developed to the acute effects of the opioid. Correspondingly, no alterations in dopamine turnover were observed when chronic morphine-treated rats were compared with control rats acutely injected with morphine. cAMP levels in the paraventricular nucleus were unchanged during the tolerant state. The results raise the possibility that noradrenergic afferents play a significant role in the alterations of paraventricular nucleus function and pituitary-adrenal axis activity in response to acute and chronic morphine and suggest that these modifications are not mediated through adenylate cyclase activation. The present data provide further support for the idea of adaptive changes in noradrenergic neurons projecting to the paraventricular nucleus during chronic morphine exposure.

Animals↗

PubMed2000

Effects of U-50,488H and U-50,488H withdrawal on catecholaminergic neurons of the rat hypothalamus.

Previous report from our laboratory showed that morphine produces a stimulatory effect of hypothalamic noradrenaline (NA) turnover concurrently with enhanced pituitary-adrenal response after its acute injection and during withdrawal. In the present work we have studied the effects of acute and chronic administration of the kappa agonist U-50,488H as well as the influence of U-50,488H withdrawal on the activity of hypothalamic NA and dopamine (DA) neurons and on the activity of hypothalamic-pituitary-adrenal (HPA) axis. A single dose of U-50,488H (15 mg/kg i.p.) significantly increased hypothalamic NA and decreased DA turnover at the time of an enhanced corticosterone release. Rats rendered tolerant to the kappa agonist by administration of U-50,488H twice a day for 4 days showed no changes in corticosterone secretion. Additionally, a decrease in both hypothalamic MHPG (the cerebral NA metabolite) production and NA turnover was observed, whereas DOPAC concentration and DA turnover were enhanced, which indicate the development of tolerance towards the neuronal and endocrine actions of U-50,488H. After naloxone (3 mg/kg s.c.) administration to U-50,488H-tolerant rats, we found neither behavioural signs of physical dependence nor changes in hypothalamic catecholaminergic neurotransmission. In addition, corticosterone secretion was not altered in U-50,488H withdrawn rats. Present data clearly indicate that tolerance develops towards the NA turnover accelerating and DA turnover decreasing effect of U-50,488H. Importantly and by contrast to mu agonists, present results demonstrate that U-50,488H withdrawal produce no changes in hypothalamic catecholamines turnover or in corticosterone release (an index of the hypothalamus-pituitary-adrenal activity), which indicate the absence of neuroendocrine dependence on the kappa agonist. As has been proposed, this would suggest that the mu and the kappa receptor be regulated through different cellular mechanisms, as kappa agonists have a lower proclivity to induce dependence.

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

PubMed2000

Catecholaminergic activity and 3',5'-cyclic adenosine monophosphate levels in heart right ventricle after naloxone induced withdrawal.

This study evaluated the adaptive changes in noradrenergic neurons and the concomitant production of cAMP during morphine dependence and withdrawal in the right ventricle of the rat. Rats were made dependent on morphine by morphine pellet implantation for 7 days. On the day of sacrifice animals received an acute injection of saline or naloxone (1 mg/kg s.c.) and were decapitated 30 min later. Pretreatment with propranolol 15 min prior to naloxone was conducted to evaluate the possible implication of beta-adrenoceptors. The contents of noradrenaline and dopamine and their metabolites were examined. After naloxone administration to morphine-dependent rats (withdrawal) there was a pronounced increase in the content of normetanephrine and 3,4-dihydroxyphenylacetic acid and increased noradrenaline and dopamine turnover. In addition cAMP levels were increased after naloxone administration to morphine-treated rats. Propranolol did not block the hyperactivity of catecholaminergic neurons or the enhancement of cAMP observed in the heart during withdrawal. The present results indicate that heart catecholaminergic neurons play a significant role in the alterations in heart functions during morphine abstinence syndrome and suggest that those alterations are mediated through cAMP.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Beta,gamma-methylene ATP but not alpha,beta-methylene ATP mimics the inhibitory effect of ATP on ventricular automaticity.

The effects of alpha,beta- and beta,gamma-methylene ATP on ventricular automaticity induced by local injury in the right ventricle of rats pretreated with reserpine, were investigated and compared with the effects of ATP and adenosine. Beta,gamma-methylene ATP but not alpha,beta-methylene ATP mimicked the inhibitory effect of both ATP and adenosine on the spontaneous automaticity In low concentrations, adenosine was more effective than ATP. Alpha,beta-methylene ATP caused little or no effect on ventricular automaticity. The results suggest that the effect of ATP might depend on its hydrolysis into AMP/adenosine.

Adenosine Triphosphate↗

PubMed2000

Autoradiographic evidence of delta-opioid receptor downregulation after prenatal stress in offspring rat brain.

In order to visualize neuroanatomical alterations in specific brain regions, light microscopy autoradiography was carried out on offsprings (postnatal day 10) from female rats stressed in different periods of gestation and controls. Group 1 was subjected to restraint stress from day 2 to 6; group 2, from day 7 to 11; group 3, from day 12 to 16; group 4 from day 2 to 16. Group 2 showed decreases in delta-opioid receptor density in different hypothalamic regions. The decrease in delta-opioid receptor density was less marked in groups 1 and 3 whereas there was no modification in group 4. Present data suggest that the prenatal stress induces a downregulation of delta-receptors in different hypothalamic regions.

Animals↗

PubMed2000

Noradrenergic and dopaminergic activity in the hypothalamic paraventricular nucleus after naloxone-induced morphine withdrawal.

Previous research has shown an increase in hypothalamo-pituitary-adrenal axis activity following naloxone administration to morphine-dependent rats. In the present study, we investigated the adaptive changes in the noradrenaline (NA) and dopamine (DA) systems in the hypothalamic paraventricular nucleus (PVN) during morphine dependence and withdrawal. Additionally, we examined the possible change in 3',5'-cyclic adenosine monophosphate (cAMP) levels in that nucleus under the same conditions. Rats were made dependent on morphine by morphine or placebo (naïve) pellet implantation for 7 days. On day 8, rat groups received an acute injection of saline or naloxone (1 mg/kg subcutaneously) and were decapitated 30 min later. NA and DA content as well as their metabolite production in the PVN were estimated by HPLC/ED. Both plasma corticosterone levels and cAMP concentration in the PVN were measured by RIA. Naloxone administration to morphine-dependent rats (withdrawal) induced a pronounced increase in the production of both the NA metabolite MHPG and the DA metabolite DOPAC and an enhanced NA and DA turnover. Furthermore, an increase in corticosterone secretion was observed in parallel to the changes in catecholamine turnover. However, no alterations in cAMP levels were seen during morphine withdrawal. These results raise the possibility that catecholaminergic afferents to the PVN could play a significant role in the alterations of PVN functions and consequently in the pituitary-adrenal response during morphine abstinence syndrome. These data provide further support for the idea of adaptive changes in catecholaminergic neurons projecting to the PVN during chronic morphine exposure.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Activation of c-fos expression in hypothalamic nuclei by mu- and kappa-receptor agonists: correlation with catecholaminergic activity in the hypothalamic paraventricular nucleus.

Administration of the preferential mu-opioid receptor agonist, morphine, and selective K-opioid receptor agonists elicits activation of the hypothalamus-pituitary-adrenocortical axis, although the site or the molecular mechanisms for these effects have not been determined. The expression ofFos, the protein product of the c-fos protooncogene, has been widely used as an anatomical marker of monitoring neuronal activity. In the present study we evaluated 1) the effects of the mu-opioid receptor agonist, morphine, and those of the selective K-opioid receptor agonist, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl-]benzeneacet amide methane sulfonate (U-50,488H), administration on the expression of Fos in hypothalamic nuclei; and 2) the possible modification of the activity of noradrenergic neurons known to send afferent projections to the paraventricular nucleus (PVN), the site of CRF neurons involved in initiating ACTH secretion. Using immunohistochemical staining of Fos, the present results indicate that acute treatment with either morphine or U-50,488H induces marked Fos immunoreactivity within the hypothalamus, including the medial parvicellular PVN and supraoptic and suprachiasmatic nuclei. Pretreatment with naloxone attenuated the effect of morphine, whereas nor-binaltorphimine, a selective kappa-opioid receptor antagonist, abolished the effect of U-50,488H on Fos induction. Correspondingly, morphine and U-50,488H injection increased the production of the cerebral noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol as well as noradrenaline turnover in the PVN. These effects were antagonized by naloxone and nor-bin-altorphimine, respectively. All of these findings are discussed in terms of specific events that couple opioid-induced activation of the hypothalamus-pituitary-adrenocortical axis and noradrenergic activity with changes in gene expression in selective hypothalamic nuclei.

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

PubMed2000

Changes in catecholaminergic pathways innervating paraventricular nucleus and pituitary-adrenal axis response during morphine dependence: implication of alpha(1)- and alpha(2)-adrenoceptors.

We have previously shown an enhanced activity of the pituitary-adrenal response in rats dependent on morphine, which occurs concomitantly with an increase in the activity of catecholaminergic terminals in the hypothalamic paraventricular nucleus (PVN). The present study examined the possible role of noradrenergic system in the regulation of opioid withdrawal-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis activity. Rats were given morphine by s.c. implantation of morphine pellets for 7 days. On the seventh day, morphine withdrawal was induced by s.c. administration of naloxone (1 mg/kg), rats were sacrificed 30 min later, and changes in noradrenaline (NA) turnover (estimated by the 3-methoxy-4-hydroxyphenylethylen glycol/NA ratio) and in dopamine turnover (estimated by the 3,4-dihydroxyphenylacetic acid/dopamine ratio) in the PVN (HPLC with electrochemical detection) and in plasma corticosterone levels were determined. We found a parallelism between the behavioral signs of withdrawal, an increased activity of noradrenergic and dopaminergic terminals in the PVN, and the hypersecretion of the HPA axis. Pretreatment with alpha(1)- or alpha(2)-adrenoceptor antagonists prazosin or yohimbine, respectively, 15 min before naloxone administration significantly prevented the withdrawal-induced corticosterone hypersecretion and attenuated the behavioral signs of morphine withdrawal. In addition, biochemical analysis indicated that both prazosin and yohimbine completely abolished the withdrawal-induced increase in NA turnover in the PVN. In contrast, neither prazosin nor yohimbine modified the hyperactivity of dopaminergic terminals in the PVN during withdrawal. Collectively, these data suggest that the secretory activity in the HPA axis after morphine withdrawal results from an increase in noradrenergic activity that is dependent on alpha(1)- and alpha(2)-adrenoceptor activation. Activation of dopaminergic pathways might not contribute to the neuroendocrine response during withdrawal.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1999

Effects of morphine and U-50,488H on neurochemical activity of the hypothalamic noradrenergic neurons and pituitary-adrenal response.

We examined the ability of morphine and U-50,488 H administered acutely to the rat to modify the hypothalamic noradrenaline (NA) content and turnover as well as corticosterone release. Hypothalamic NA and its metabolite 3-methoxy-4-hydroxy-phenylethylen glycol (MHPG) were determined by high-performance liquid chromatography (HPLC). Plasma corticosterone was measured by radioimmunoassay (RIA). The administration of morphine (30 mg/kg i.p.) induced a decrease in the hypothalamic content of NA, with an enhancement in the MHPG and the MHPG/NA ratio. Similarly, the administration of U-50,488 H (15 mg/kg i.p.) produced an increase in the MHPG and MHPG/NA ratio without any changes in the NA content. The present results also show that corticosterone secretion was increased after acute morphine or U-50,488 H, in parallel with an enhanced NA turnover and strongly suggest that noradrenergic neurons have stimulatory effects on the HPA axis activity, reflecting an indirect action of opioid on the axis through hypothalamic catecholaminergic systems.

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

PubMed1999

Catecholaminergic activity and 3',5'-cyclic adenosine monophosphate concentrations in the right ventricle after acute and chronic morphine administration in the rat.

We have examined possible regulation of norepinephrine and dopamine concentrations and turnover in the right ventricle of the rat after acute administration of saline i.p. or morphine 30 mg kg-1 i.p. to placebo (naïve) or morphine (tolerant) pretreated rats. We also assessed concentrations of 3',5'-cyclic adenosine monophosphate (cAMP) in the right ventricle after the same treatments. Concentrations of catecholamines and their metabolites in the heart were measured by high-pressure liquid chromatography with electrochemical detection (HPLC/DE). Concentrations of cAMP in the heart were measured by radioimmunoassay (RIA). Administration of morphine to naïve rats did not modify concentrations of norepinephrine (NE), normetanephrine (NMN) or NMN/NE ratio in the right ventricle. However, dopamine concentrations increased whereas dopamine turnover decreased. In addition, cAMP concentrations decreased after acute administration morphine to naïve rats. In rats pretreated with morphine chronically, there was an increase in norepinephrine concentrations with no change in normetanephrine concentrations or norepinephrine turnover after acute injection of morphine. In contrast, dopamine turnover increased in the tolerant groups after acute injection of saline or morphine compared with the nave group given morphine, indicating that tolerance develops to the acute effects of the opioid. Concentrations of cAMP increased after chronic morphine administration. Our results demonstrate that chronic morphine pretreatment leads to up-regulation of the cAMP system in the heart and suggest that this up-regulation may be involved in the cellular mechanisms implicated in the adaptive changes of dopaminergic neurones in the heart observed during chronic treatment with morphine.

Analgesics, Opioid↗