Changes in brain tryptophan and tyrosine following acute and chronic morphine administration

Morphine increased brain concentrations of tryptophan and tyrosine 1–2 hr after administration in a dose-dependent manner in male rats. Concentrations of these amino acids in blood serum decreased 30–45 min post-injection and then rose towards control values. The rise in brain amino acids was antagonized by pretreatment with naloxone. In addicted rats there was only a slight increase in brain tryptophan and no increase in tyrosine. Thirty minutes after naloxone-precipitated withdrawal, tryptophan and tyrosine concentrations were elevated in brain, in contrast to the decline in these amino acids seen after naloxone administration in acutely morphinized rats.These results support the hypothesis that the elevated turnover of brain monoamines induced by morphine administration is related to increased availability of precursor amino acids in morphinized animals.     

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.     

Circadian oscillation in rat liver tyrosine aminotransferase activity after chloroform inhalation.

Determination of tyrosine aminotransferase activity in the liver of rats exposed for 2 min to a chloroform atmosphere showed an adaptive increase in the activity of the enzyme, with a maximum plateau between 4–6 hr after initiating the stress. The amplitude of the adaptive response differed in terms of the circadian rhythm of the enzyme, the periods of intense basal activity being characterized by the lowest reactivity.     

Prostaglandins in rat placenta following acute and chronic administration of morphine.

The objective of the present study was to obtain information on prostaglandin (PG) biosynthesis in placenta following narcotic administration. PG biosynthetic capacity was determined in whole rat placenta homogenates in the presence of Na arachidonate, by evaluating net production of PGs assayed against PGE1 on rat stomach strips. An enhanced prostaglandin-like activity is shown in homogenates of placenta from rats treated subcutaneously with 10 mg/kg of morphine. This increase was prevented by naloxone pre-treatment. Continual morphine administration during gestation, results in a normalization of placental biosynthetic capacity thus suggesting the development of a tolerance to the narcotic effect.     

Modification of serotonin metabolism in rat brain after acute or chronic administration of morphine

The steady state concentration of 5-hydroxyindoleacetic acid (5-HIAA) was elevated in rat brain for at least 4 hr after administration of a single dose of morphine sulfate (30 mg/kg, s.c.), and for more than 40 hr after subcutaneous implantation of pellets of morphine alkaloid. The concentration of 5-HIAA returned to normal 3 days after pellet implantation at a rate that paralleled the development of tolerance to the analgesic and other overt actions of morphine. Morphine did not modify the steady state concentration of serotonin under any of the treatment conditions. The turnover of brain serotonin was increased significantly during the 90-min period following a single injection of morphine sulfate (30 mg/kg, s.c.), as indicated by an increased rate of accumulation of 5-HIAA after blockade of efflux of 5-HIAA by probenecid in morphinetreated animals. As judged either by the rate of accumulation of 5-HIAA after administration of probenecid, or by the rate of accumulation of serotonin after treatment with pargyline, an increase in turnover of serotonin was evident in brains of tolerant rats 72 hr after pellet implantation. The rate of efflux of 5-HIAA from the brain was the same in control and morphine-tolerant rats. These results indicate that changes in brain serotonin metabolism are associated with both the acute effects of morphine and with morphine tolerance.     

Effects of morphine on isoenzymes of pyruvate kinase and tyrosine aminotransferase in rat.

The acute and chronic effects of morphine on isoenzymes of pyruvate kinase and tyrosine aminotransferase in rat liver have been studied in vivo. Acute administration of morphine inhibits the L-type pyruvate kinase but increases forms II, III and IV of tyrosine aminotransferase in rats which have received a single intraperitoneal injection of morphine 6 hr prior to sacrifice. However both effects are lost after 24 hr. Morphine starts to regain its stimulatory effect on tyrosine aminotransferase at the hr 48 and reaches a maximum at the hr 72. Chronic morphinization leads to similar changes in the total activities of pyruvate kinase and tyrosine aminotransferase but the change in isoenzyme pattern of tyrosine aminotransferase concerns only forms II and III. Results from this study support the hydrocortisone-like property of morphine and indicate that morphine may enhance gluconeogenesis in vivo.     

The effect of acute and chronic administration of morphine and morphine withdrawal on intestinal transit time in the rat

The effects of acute and chronic morphine administration and of morphine-withdrawal on intestinal transit time of a liquid meal were investigated using rats. Many experiments have assessed the effects of acute morphine administration on intestinal transit, but the intestinal effects of chronic morphine administration have been neglected. Our results showed no significant differences between morphine-dependent and control animals when assessing the leading edge of the liquid meal infusion, its distribution and geometric centre (G.C.). However, during naloxone-precipitated withdrawal from morphine, the leading edge of the infusion and its G.C. were significantly distal to values obtained from other groups. Acute morphine administration caused delayed intestinal transit of a meal infusion, an effect partly caused by significant retention of the infusion in the stomach and duodenum. The leading edge of the meal infusion and G.C. were significantly proximal to values obtained from other groups of animals. The results show that morphine-dependent rats develop complete tolerance to the delayed intestinal transit of a meal observed after acute morphine administration and that withdrawal from morphine accelerates intestinal transit of a liquid meal.     

Changes in stimulation analgesia during chronic morphine administration

It has been shown in rat experiments that repeated administration of morphine produces tolerance to the effect of stimulation analgesia (SA). In the control group, the same stimulation of the periaqueductal gray matter (PGM) failed to produce tolerance. Naloxone (2 mg/kg i.p.) exerted a partially antagonistic influence on SA in the control group and did not affect the antinociceptive action of PGM stimulation in morphine-treated animals.     

Reduced inactivation of tyrosine aminotransferase in the prefused rat liver in the presence of ethanol.

The mode of action whereby alpha-methyltyrosine (alpha-MT) potentiates the behavioural effects induced by catecholamine receptor blocking antipsychotic drugs was investigated in rats trained to lever-press for food on a fixed-ratio 40 schedule of reinforcement. It was found that alpha-MT (20 mg/kg intraperitoneally -- 4 hrs potentiates the effects induced by pimozide (0.04 mg/kg intraperitoneally -- 6 hrs) which preferentially blocks central dopamine (DA) receptors, but not the effects induced by phenoxybenzamine (0.5 mg/kg intraperitoneally -- 30 min.) which blocks central noradrenaline (NA) receptors. Furthermore, the behavioural suppression induced by chlorpromazine (0.5 mg/kg intraperitoneally -- 15 min.), thioridazine (1.5 mg/kg intraperitoneally -- 15 min.), or haloperidol (0.02 mg/kg intraperitoneally -- 15 min.) were not potentiated by the administration of the inhibitor of DA-beta-hydroxylase, bis-(4-methyl-1-homopiperazinylthiocarbonyl) disulfide (FLA-63) 4 mg/kg subcutaneously -- 1 hr). The potentiation by alpha-MT of the clinical effects of antipsychotic drugs and of their behavioural effects in animal experiments is in all probability due to a blockade by alpha-MT of a feed-back mediated compensatory increase in the catecholamine synthesis as a result of a blockade of central NA and/or DA receptors by the antipsychotic drugs. Since, in the present experiments, the behavioural effects induced by drugs which block central DA but not NA receptors were potentiated by the simultaneous administration of alpha-MT, it seemed probable that the disruption of conditioned behaviours by antipsychotic drugs is due to a blockade of central DA receptors. In view of the fact that the ability to selectively disrupt conditioned behaviours is shared by a wide range of antipsychotic drugs differing in chemical structure and also in their mode of action, it is possible that a blockade of DA neurotransmission is also of primary importance for the clinical effects induced by antipsychotic drugs.     

Changes in sleep after acute and repeated administration of nicotine in the rat

Rationale: Acetylcholine clearly plays a role in regulating sleep. This influence may involve nicotinic systems because several studies have demonstrated that nicotine treatment alters sleep. However, the literature that suggests an effect of nicotine treatment on sleep is contradictory, perhaps because different doses and routes of administration were used. Objective: The studies reported here evaluated the effects of several doses of nicotine on REM sleep in the rat. Methods: Male Wistar rats were prepared with a set of sleep recording electrodes and, following habituation to the test chamber, were used in one of three studies: a) a dose-response analysis of an acute dose of nicotine on REM sleep measured during the first 4 h after injection; b) a chronic treatment experiment; or c) a mecamylamine blockade experiment. Results: Acute nicotine administration decreased REM sleep in a dose-dependent fashion; significant effects were observed following injection with the 0.5 and 1.0 mg/kg doses. A decrease in slow wave sleep and an increase in wakefulness were also observed. Mecamylamine by itself did not affect REM sleep, but it blocked the effects on sleep produced by nicotine when given 30 min before a 1 mg/kg dose of nicotine. Rats that had been injected once daily with a 0.1 mg/kg dose of nicotine showed an increase in REM sleep after the third injection, whereas rats that had been chronically treated with a higher dose (0.5 mg/kg) displayed a reduction in REM and total sleep time. Conclusion: These findings argue that the effects of both acute and chronic nicotine treatment on sleep are influenced by the dose of nicotine used. Received: 7 July 1998 / Final version: 9 March 1999     

Pteroylpolyglutamate pool modifications in rat liver after chronic administration of phenobarbitone and valproate.

Chronic intraperitoneal administration of low doses of phenobarbitone and valproate caused different alterations in hepatic percentage distribution of pteroylpolyglutamate derivatives without modification of total folate content. Phenobarbitone treatment caused a significant decrease of the percentage content of reduced unsubstituted and methylene-substituted derivatives, while valproate produced an increase of the percentage content of methenyl-, formyl- and formimino-substituted derivatives and a concomitant percent increase of hexaglutamates. The modified ratios of various pteroylpolyglutamates, both in phenobarbitone- and in valproate-treated animals, probably contribute to influencing the partitioning of the one-carbon pool through the various areas of one-carbon metabolism.     

Changes in sulfhydryl compounds in plasma, liver and brain after acute and chronic acetaldehyde administration in rats

The content of sulfhydryl compounds in proteins and non-proteins of plasma, liver and brain after acute and chronic administration of acetaldehyde (ACH) was investigated in rats. After ACH 1.5% w/v ingestion for 1 and 4 weeks (0.3 ml/kg) daily, proteins and non-proteins in plasma and liver were decreased significantly. After acute ACH administration SH-groups in brain proteins were not significantly decreased, but in the brain non-proteins these groups were increased significantly.     

Effect of halopredone acetate on rat liver tryptophan oxygenase and tyrosine aminotransferase activities.

The possible inductive effect of a new local antiinflammatory steroid, 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate; Topicon), on the rat liver enzymes tryptophan oxygenase and tyrosine aminotransferase was evaluated. The new steroid, when present in the implanted cotton-pellets or when s.c. injected, unlike the reference compound, fluocinolone acetonide, which induced a large increase in both enzymes, did not modify either tryptophan oxygenase or tyrosine aminotransferase. The results confirm that halopredone acetate elicits potent local antiinflammatory activity in the absence of systemic effects.     

Changes in rat carbohydrate metabolism after acute and chronic treatment with dichlorvos.

Administration to rats of a single dose of dichlorvos (DDVP) equal to 50% of the LD50 caused hyperglycemia which could be prevented, and the effect of the pesticide completely abolished, by administration of increasing doses of insulin. The glucose tolerance curves after po administration of glucose showed impaired regulation of carbohydrate metabolism and changes of the diabetic type. A statistically significant increase in glycogen phosphorylase activity was observed after administration of a single dose (50% LD50) of DDVP. UDPglucose pyrophosphorylase activity was decreased both after acute treatment and after administration of DDVP (5% of the LD50 daily) for 3 or 7 days, but the enzyme activity became adapted to the pesticide after 14 days of treatment with low doses of DDVP. In experiments in vitro, dichlorvos (at concentration of 10^?4, 10^?3, and 10^?2m) stimulated the glycogen phosphorylase activity in liver extract only after 30-min preincubation. Dichlorvos inhibited synthesis of UDPglucose from UTP and G-1-P but only at concentrations as high as 10^?3 and 10^?2m. Changes in glycogen synthetase activity were observed only at a very high dichlorvos concentration (10^?2m).