M. Luisa Vargas

Plasma β-endorphin and cortisol levels in morphine-tolerant rats and in naloxone-induced withdrawal

The relationship between morphine tolerance and pituitary-adrenocortical activity was examined. In rats made tolerant to morphine by implantation of morphine-containing pellets, there was a significant reduction in plasma levels of beta-endorphin-like immunoreactivity (beta-END-LI), whereas no significant changes in cortisol levels were seen. Naloxone treatment induced an increase in plasma beta-END-LI and cortisol levels in morphine-tolerant animals. Additionally, acute morphine administration induced an increase in plasma levels of beta-END-LI and cortisol, an effect which was prevented by naloxone. These results are consistent with an increased release of pro-opiomelanocortin-derived peptides after acute morphine and with a decreased release of these peptides in tolerant rats, and suggest that opioid peptides play an important role in the regulation of pituitary-adrenocortical function.

Effects of acute and chronic administration of μ- and δ-opeoid agonists on the hypothalamic-pituitary-adrenocortical (HPA) axis in the rat

Abstract 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 μ- and δ-opioid agonists, administered centrally (i.c.v.), on pituitary-adrenocortical activity in the rat. The μ-agonist DAGO ([D-Ala2,N-MePhe4,Glyol]enkephalin; 0.75 nmol i.c.v.) and the δ-agonist DPDPE ([D-Pen2.5enkephalin; 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 μ- and δ-opioid receptors are involved in the regulation of HPA activity under physiological conditions and during opiate abuse.

Catecholaminergic mediation of morphine-induced activation of pituitary-adrenocortical axis in the rat: implication of α- and β-adrenoceptors

Abstract 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 α 1 -andα 2 -antagonists prazosin and yohimbine, respectively, significantly antagonized the effect of morphine on plasma corticosterone. The β-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 α 1 -, α 2 -andβ-adrenoceptors .

Pituitary-adrenocortical response to acute and chronic administration of U-50,488H in the rat.

K-opioid substances have been shown to stimulate and/or depress the HPA activity. The objective of this study was to determine the effects of the acute and chronic administration of U-50,488H, a k-opioid receptor agonist, on the pituitary-adrenocortical activity in the rat. The acute administration of U-50,488H (25 mg/kg i.p.) produced a hypothermic effect and an increase in plasma levels of B-END-LI and cortisol, effects which were prevented by naloxone (3 mg/kg s.c.). Chronic administration of U-50,488H twice a day for 4 days resulted in a decrease in basal plasma levels of B-END-LI and cortisol and in the development of tolerance to its neuroendocrine and hypothermic effects. In rats made tolerant to U-50,488H, naloxone precipitated hypothermia (which is an index of opiate dependence in rats), whereas no changes in plasma B-END-LI and cortisol levels were seen. These data suggest that k receptors may be involved in the regulation of pituitary-adrenocortical activity in physiological conditions and during opiate abuse. On the other hand, U-50,488H induced only negligible dependence in rats, which was not morphine-like.

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.

Effects of rolipram and diazepam on the adaptive changes induced by morphine withdrawal in the hypothalamic paraventricular nucleus

A role for the cyclic AMP systems in the development of morphine dependence has been previously reported. In this study we investigated whether morphine dependence was inhibited by phosphodiesterase (PDE) 4 inhibitors rolipram and diazepam. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. On day 8, morphine withdrawal was precipitated by an injection of naloxone. In order to determine the effect of rolipram and diazepam rats were injected with these drugs once daily for seven days as well as 30 min before of naloxone injection. When opioid withdrawal was precipitated, an enhanced noradrenaline turnover and increased level of cyclic AMP and cyclic GMP in the hypothalamic paraventricular nucleus (PVN) were observed 30 min after naloxone administration. Moreover, c-Fos expression was induced in the PVN after naloxone-precipitated morphine withdrawal. Co-administration of rolipram or diazepam with morphine during the pre-treatment period, significantly reduced the signs of withdrawal, the enhancement of noradrenaline turnover and the increase in cyclic AMP. However, these inhibitors did not modify either levels of cyclic GMP or c-Fos expression in the PVN. These findings demonstrate that co-administration of rolipram or diazepam with morphine attenuate the withdrawal syndrome and suggest that these compounds may prevent the up-regulation of the cyclic AMP pathway and the associated increase in cyclic AMP level in morphine-withdrawn rats.

Involvement of κ-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)

Influence of Dopaminergic and Noradrenergic Systems on the Release of Opioid Peptides in Guinea‐pig Ileum

Neuroleptic drugs increase the biosynthesis and release of opioid peptides from the myenteric plexus of guinea‐pig ileum. In the present work, the involvement of dopamine receptors or α‐adrenoceptors in the release of opioids from the myenteric plexus of guinea‐pig was investigated. Acute or chronic treatment with prazosin, an α1‐blocking drug, produced no changes in the release of these peptides. Release was also unchanged after acute or chronic treatment with the α2‐blocking drug yohimbine. However, treatment with domperidone, a selective dopamine receptor antagonist, resulted in an increase in the release of opioids, as did treatment with (‐)−3−(3−hydroxyphenyl)‐N‐n‐propylpiperidine ((‐)−3−PPP), a dopamine autoreceptor stimulant. It is concluded that the effect of neuroleptics on the release of opioids from myenteric plexus is due to the blockade of dopamine receptors, and that interruption of dopaminergic transmission produces an increase in opioid release at this level.

Pharmacological evidence for the existence of interactions between dopaminergic and opioid peptidergic systems in guinea-pig ileum myenteric plexus

Apomorphine or bromocriptine treatment at doses that act on dopamine autoreceptors resulted in a significant elevation of the release of opioid peptides from the myenteric plexus of guinea-pig, since these drugs produced an increase of the inhibitory response which was reversed by naloxone. 6-Hydroxydopamine treatment also resulted in an increase in opioid peptide release. These findings would indicate that the interruption of dopaminergic transmission in the myenteric plexus produces an increase in the release of opioid peptides and suggest an inhibitory modulation of opioid peptidergic neurons by dopamine systems at this level.

Stress and morphine mediated changes in pituitary-adrenal axis in guinea-pigs.

1. Changes in plasma levels of B-END and cortisol were investigated in guinea-pigs receiving either stressful stimuli for various lengths of time or i.p. injections of morphine or saline. 2. A decrease in B-END levels occurred when animals were stressed, whereas cortisol was not affected. 3. Morphine (50 mg/kg i.p.) enhanced B-END and cortisol levels 5 min after injection, whereas a decrease in B-END was seen at 30 min. 4. Saline (i.p.) produced a decrease of B-END levels 30 min after injection and an increase in cortisol 5 and 10 min after injection. These findings suggest that in the guinea-pig the response of pituitary-adrenal axis to stress or morphine could change depending upon the time of sampling.