Effect of substituted benzamides on feeding and hypothalamic neuropeptide Y-like immunoreactivity (NPY-LI) in rats.

The study was conducted: (i) to evaluate the effects of three substituted benzamides on feeding behaviour in rats with free access to food and in those with access to food limited either to the light or to the dark phase of the diurnal cycle; and (ii) to determine whether the hypothalamic neuropeptide Y (NPY) system is involved in the action of these drugs on feeding. In free-feeding rats, a single dose of eticlopride (1 mg/kg, i.p.) or raclopride (1 mg/kg, i.p.) decreased 24-h food intake, whereas remoxipride (3 mg/kg, i.p.) produced no effect. Single doses of eticlopride and raclopride but not of remoxipride decreased hypothalamic neuropeptide Y-like immunoreactivity (NPY-LI). Eticlopride administered once daily for 14 days decreased both food intake and hypothalamic NPY-LI. When given for 14 days, raclopride and remoxipride decreased food intake in rats with access to food in the dark (19.00-07.00) but not in thelight (07.00-19.00) phase of the diurnal cycle; both these compounds decreased hypothalamic NPY-LI only in the former group of rats. The results suggest that the effects of substituted benzamides on feeding behaviour depend on the drug and the time of administration and that these effects are related to the altered function of the hypothalamic NPY system.

Effect of enflurane on selected neuropeptides and marker enzymes in rabbit brain.

The aim of this study was to evaluate the effect of 5-, 15-, and 60-min enflurane anesthesia on the levels of Met-enkephalin, Leu-enkephalin and neuropeptide Y in discrete areas of the rabbit brain. We also evaluated the effect of enflurane anesthesia on energetic, transport and catabolic processes by measuring the activities of succinate dehydrogenase, magnesium-dependent adenosine triphosphatase and acid phosphatase in the rabbit striatum and hypothalamus. Induction of anesthesia (5 min) decreased Met-enkephalin levels in the hypothalamus and striatum, and increased them in the hippocampus and mesencephalon. Induction of anesthesia increased Leu-enkephalin levels in all brain areas studied, except for the striatum, and increased neuropeptide Y content in the hippocampus. 15- and 60-min enflurane anesthesia increased Met-enkephalin content in the hypothalamus and hippocampus. After 15- and 60-min anesthesia, and after cessation of anesthesia, Leu-enkephalin levels were increased in the hypothalamus and mesencephalon, and were decreased in the striatum and hippocampus. In the striatum, neuropeptide Y content was significantly decreased during anesthesia and after cessation of anesthesia. Histochemical analysis revealed that enflurane enhanced ATP production, catabolic processes, and the rates of exchange and transport of energetic substrates in the striatum and hypothalamus. In conclusion, enflurane affects the levels of Met, Leu-enkephalins and NPY in a manner depending on the duration of anesthesia and the brain structure. Compared with isoflurane , which was studied in our previous study enflurane produces stronger alterations in the activities of enzymatic marker in the rabbit brain. This suggests that enflurane may be less safe than isoflurane.

Influence of isoflurane on enkephalin levels and on some indicatory enzymes in the central nervous system of rabbits.

The objective of this study was to analyse the effects of isoflurane anesthesia (lasting for 15 or 60 min) and isoflurane anesthesia termination (after 1 or 24 h) on met-enkephalin (MENK) and leu-enkephalin (LENK) levels in discrete brain areas and spinal cord segments in rabbits. Moreover histochemical analysis of activities of succinate dehydrogenase, magnesium-dependent adenosine triphosphatase (Mg++ATP-ase) and acid phosphatase in the striatum and hypothalamus were carried out to evaluate the effects of isoflurane anesthesia on energetic, transport and catabolic processes. Throughout anesthesia (15 and 60 min) and after its termination (1 h) the LENK contents were increased in hypothalamus, hippocampus, mesencephalon and lumbar segment of spinal cord. Moreover, during isoflurane anesthesia and after its termination (1 h) MENK and LENK levels decreased in cervical segment and MENK content dropped in thoracic segment of spinal cord. Histochemical data indicated, that isoflurane enhanced energetic processes as well as exchange processes in neurocytes, glial cells, capillary walls and ependymal cells of the third ventricle. Measurements of acid phosphatase activity provided evidence of no signs of toxicity of isoflurane in the examined areas. The changes in enkephalin levels observed during the isoflurane anesthesia and after its termination depended on the type of examined neuropeptides, as well as on parts of the brain and spinal cord studied. The changes observed after isoflurane administration in enkephalinergic system are discussed with regard to our earlier experiments with halothane and enflurane.

Antagonistic effect of MR2266 and MR2267 on morphine or nalbuphine analgesia at the spinal levels in rats.

The aim of this paper was to study the effect of two benzomorphan derivatives MR2266 and MR2267 with predominant antagonism to kappa-opioid receptors administered intrathecally on the analgesic action of morphine and nalbuphine. Both compounds attenuated the analgesia elicited by examined opioid agonists. Our results support the hypothesis that the spinal opioid receptors take part in analgesic effect of morphine and nalbuphine. It was for the first time described that MR2267, considered as inactive enantiomer of MR2266, is an active opioid antagonist when administered intrathecally.

Influence of halothane on the level of enkephalins in discrete brain areas of rabbits.

With regard to the fact, that theory of anesthesia, based on the endogenous opioid peptides requires further investigations the aim of this paper was to measure the concentration of leucine- (LENK) or methionine-enkephalin (MENK) in discrete brain areas of rabbits during and after 1 h halothane (2% v/v) anesthesia. The level of LENK and MENK was measured in discrete brain areas using the radioimmunoassay. Animals were divided into the following groups, depending upon the duration of anesthesia: I-15 min; II-60 min; III-1 h after anesthesia termination; IV-control group of non-anesthetized animals. After halothane anesthesia evident decrease in the concentration of leu-enkephalins in hypothalamus (HT) and the opposite effect in hippocampus (H) were observed. The MENK level significantly increased after halothane (for 60 min) in hypothalamus, hippocampus and mesencephalon (M). The change in the level of LENK in the thalamus (Th), hippocampus and mesencephalon and in the level of MENK in the hypothalamus and mesencephalon persisted after withdrawal of anesthesia. It was found that the alterations in the level of enkephalins in discrete areas of rabbit's brain is a feature of halothane anesthesia. The explanation of this phenomenon is possibly important for the understanding of the mechanism of halothane anesthesia and requires further investigations.

Influence of ketamine and its interactions with morphine and nalbuphine on the level of enkephalins in some parts of the brain and spinal cord.

The aim of this paper was to study the influence of ketamine in a dose of 80 or 160 mg/kg ip on the level of leu-enkephalin (LENK) or met-enkephalin (MENK) in some parts of the brain and spinal cord, as well as to examine the interaction of ketamine with morphine or nalbuphine on this effect. The influence of ketamine on enkephalins release into the brain perfusate was also studied. Ketamine decreased the spinal cord enkephalins concentration mainly in cervical and lumbar part. These effect was antagonized by naloxone. Ketamine administered in a higher dose increased LENK release, and decreased the release of MENK into the brain perfusate. Morphine (20 mg/kg ip) increased the level of LENK in the hypothalamus, decreased the concentrations of MENK in the medulla oblongata and in the cervical part of the spinal cord, and increased the level of this neuropeptide in the thoracic part of the spinal cord. These effects were antagonized by ketamine. Ketamine and morphine administered simultaneously affected the level of enkephalins in some of the studied parts of the brain and spinal cord. Nalbuphine administered in doses ranging from 1 to 20 mg/kg changed the level of enkephalins in some parts of the central nervous system. Ketamine and nalbuphine administered simultaneously changed the level of enkephalins in the spinal cord and in the hypothalamus. It is concluded that: the decrease of the level of enkephalins in the spinal cord is an evident feature of ketamine action mediated probably by opioid receptors. Ketamine affects the release of LENK and MENK from the brain in a different way.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic treatment with chlorpromazine, thioridazine or haloperidol increases striatal enkephalins and their release from rat brain.

The aim of this paper is to study the effect of 1, 2 or 3 months' administration of chlorpromazine (CPZ), thioridazine (TDZ) (2 or 6 mg/kg) or haloperidol (HAL) (0.25 or 1 mg/kg) IP on the level of leu- and met-enkephalin (ENK) in striatum. A dose- and time-dependent increase of striatal ENK level was observed after chronic administration of the neuroleptics (NL), but 8 days after withdrawal of chronically administered NL striatal ENK was decreased. Apomorphine pretreatment significantly attenuated the elevation in ENK produced by chronic injections of NL. In perfusion fluid obtained from the lateral ventricle of animals treated 1 month with HAL a dose-dependent increase of ENK levels was observed, which was augmented by potassium ions. It is concluded that: 1) Chronic administration of neuroleptic drugs that block dopamine receptors increases the level and the release of striatal enkephalins; 2) The results support the hypothesis that activation of dopaminergic neurons tonically inhibits the synthesis of enkephalins in the striatum.

Basic pharmacological properties of a novel antiinflammatory drug tryptamide.

In rats and mice the basic pharmacological properties of tryptamide (TRP), a novel antiinflammatory substance were studied. The LD50 doses were for male rats 1260 mg/kg ip or 8.5 g/kg po, for male mice: 1980 mg/kg ip or 9.3 g/kg po. TRP produced evident antiinflammatory effects of potency comparable with those of phenylbutazone when studied by means of carrageenin-induced rat paw oedema and prostaglandin synthetase activity in vitro. TRP reversed pyrogen-induced hyperthermia in rats, elicited analgesic effects in rats, but not in mice, prolonged the time of hexobarbital sleep in rats and inhibited locomotor activity in rats and mice. TRP has not elicited side effects on the circulatory system of rats and cats. It is concluded that TRP may undergo clinical trials as a potential antiinflammatory drug. During these trials the attention should be paid to possible central side effects the drug.

Concentration of biogenic amines and their metabolites in different parts of brain after experimental cerebral concussion.

The levels of biogenic amines and their metabolites were determined in different parts of brain or cerebral-spinal fluid 0.5, 1, 6, 12 or 24 h after experimental cerebral concussion. Cerebral concussion in the rat leads within 6 h to an increase in 5-hydroxytryptamine and a decrease in dopamine utilization in the striatum. That imbalance between the functional state of serotoninergic and dopaminergic neurons may partly explain the development of vasospasms, ischemia and edema brought about by the brain mechanical trauma. Moreover, after cerebral concussion an evident decrease in NA level in discrete brain areas and a decreased DA release in the whole brain occur. In conclusion it is suggested that the alterations of catecholamine and 5-hydroxytryptamine utilization in discrete brain areas, especially in the striatum are the characteristic feature of disturbances after experimental brain concussion.

Involvement of the central serotoninergic system in the changes of leu-enkephalin level in discrete rat brain areas.

The effects of acute and chronic treatment with LSD and acute treatment with mescaline, m-CPP, citalopram and fenfluramine on leu-enkephalin (LENK) content in rat brain were examined. The acute LSD treatment was found to decrease and chronic treatment to increase the LENK content in the frontal cortex. In the thalamus with hypothalamus the LENK level fell after the administration of LSD, mescaline, citalopram and fenfluramine, while in the striatum it increased significantly, except for fenfluramine treatment. Methergoline and methiothepin prevented the effects of acute and chronic LSD administration. The diminished LENK level was associated with a decrease of 5-HT or 5-HIAA content in the rat brain areas investigated. Therefore, it has been concluded that the serotoninergic system may modulate the LENK pathway.

[Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels in the cerebrospinal fluid from the lateral ventricle of patients with brain tumors]. / Stezenie kwasu homowanilinowego (HVA) oraz kwasu 5-hydroksyindolooctowego (5-HIAA) w plynie mózgowo-rdzeniowym pochodzacym z komory bocznej mózgu u chorych z guzami mózgu.

In patients with supratentorial tumours and posterior fossa tumours or in the third ventricle the concentrations of HVA and 5-HIAA were determined in the cerebrospinal fluid from the lateral ventricle. A significantly greater concentration of HVA and 5-HIAA was found in the patients with considerable hydrocephalus caused by occlusion of the third ventricle, aqueduct or fourth ventricle as compared with the cases of supratentorial tumours and with cases of moderate hydrocephalus and partial block of fluid outflow caused by third ventricle tumorous or posterior fossa tumours.

[Biogenic amines and their metabolites in brain tumor tissue]. / Zachowanie sie amin biogennych i ich metabolitów w tkankach nowotworów mózgu.

The concentrations of noradrenaline, 5-hydroxytryptamine, dopamine, 5-hydroxyindoleacetic acid and homovanillic acid were determined in the tissue of gliomas, meningiomas and neurinomas of the brain obtained during operations. Significantly higher levels of noradrenaline and 5-hydroxyindoleacetic acid were found in gliomas than in non-malignant tumours.

Is receptor activation involved in the mechanism by which (+)-fenfluramine and (+)-norfenfluramine deplete 5-hydroxytryptamine in the rat brain?

1 The effects of (+)-fenfluramine, (+)-norfenfluramine and reserpine on the concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in brainstem and telencephalon were studied in rats treated with methergoline, a 5-HT antagonist. 2 Methergoline significantly reduced the effect of (+)-norfenfluramine (5 mg/kg) on 5-HT levels in telencephalon and brainstem but did not modify the effect of (+)-norfenfluramine (2.5 mg/kg). 3 Neither the effect of (+)-fenfluramine on 5-HT levels nor the decrease of 5-HT metabolism caused by (+)-fenfluramine and (+)-norfenfluramine was significantly modified by methergoline treatment. 4 Methergoline potentiated the effects of reserpine on brain indoles. The effects was particularly evident on 5-HIAA levels in the brainstem, although significant effects were found on 5-HT in the brainstem and 5-HIAA in the telencephalon depending on the dose reserpine used. 5 The results show that postsynaptic receptor activation may partially contribute to the depletion of brain 5-HT caused by (+)-norfenfluramine in the rat. This mechanism does not seem to play a significant role in the effect of (+)-fenfluramine.

[Homovanillic (HVA) and 5-hydroxyindoleacetic (5-HIAA) acid concentration in the cerebrospinal fluid of patients with supratentorial tumors and symptoms of intracranial hypertension (preliminary report)]. / Stezenie kwasu homowanilinowego (HVA) i kwasu 5-hydroksyindolooctowego (5-HIAA) w plynie mózgowo-rdzeniowym u chorych z guzami nadnamiotowymi i objawami nadcisnienia sródczaszkowego. Doniesienie wstepne.

In 14 patients with supratentorial tumours and symptoms of intracranial hypertension the concentrations of HVA and 5-HIAA were determined in cerebrospinal fluid obtained by lumbar tap. Significantly raised levels of both these metabolites were demonstrated in the cerebrospinal fluid in these patients in relation to controls. The cause of this rise could be excessive production of serotonin or dopamine, increased turnover of these amines or impaired absorption of 5-HIAA and HVA by the choroid plexus of the fourth ventricle.

[Disorders of dopamine and 5-hydroxytryptamine metabolism in the early period after cranio-cerebral injuries]. / Zaburzenia metabolizmu dopaminy i 5-hydroksytryptaminy u chorych we wczesnym okresie po urazach czaszkowo-mózgowych.

In patients with signs of intracranial hypertension caused by subdural haematoma or brain oedema following craniocerebral trauma significantly increased concentrations of HVA and 5-HIAA were found in the cerebrospinal fluid obtained by means of lumbar punction in relation to a control group comprising patients with lumbar disc prolapse. In patients after craniocerebral injuries with open fracture of cranial bones without disturbances of consciousness dopaminergic system hyperactivity was observed lasting up to the 7th day after injury. In patients with symptoms of brain commotion after craniocerebral trauma a significant rise in 5-HIAA concentration was observed in the cerebrospinal fluid on the 7th day after trauma. This may suggest increased serotonin turnover early after trauma.

Concentration of homovanillic acid and 5-hydroxyindoleacetic acid in the ventricular cerebrospinal fluid of patients with obstructive hydrocephalus.

In 12 patients with different posterior fossa tumours the concentrations of homovanillic acid (HVA) and of 5-hydroxyindoleacetic acid (5-HIAA) were measured in cerebrospinal fluid from the lateral ventricles. All patients had obstructive hydrocephalus. Patients with a clear increase of 5-HIAA/HVA ratio in the ventricular CSF have died subsequently. This feature may have a diagnostic value, and indicates the prevalence of serotoninergic neurones in patients with obstructive hydrocephalus with fatal course after surgery.

Potentiation of cataleptogenic effects of neuroleptics by prostaglandins.

Prostaglandins (PGs) E1, E2, F2alpha injected intracerebroventricularly (icv) in rats, potentiated chlorpromazine (CPZ) and pimozide (PI) catalepsy similarly. Cataleptogenic effect of haloperidol (HL) was potentiated specifically be PGE2. These phenomena were diminished by apomorphine (AP). Phenoxybenzamine (PB) diminished the potentiating effect of PGE2 and PGF2alpha on CPZ catalepsy, and strongly inhibited PGE2 the potentiating effect on HL and on PI catalepsy. Propranolol (PN) diminished the potentiating effect on HL and on PI catalepsy. Propranolol PN) diminished potentiating effect of PG on HL catalepsy and increased this effect of PGE1 on PI catalepsy. All examined PG induced catalepsy only when given in high doses (50 or 100 microgram icv). Cataleptogenic effect of PGE2 and PGF2 but not of PGE1, was evidently inhibited by AP. PGS inhibited AP stereotypy. The results suggest that the central dopaminergic receptors blockade is involved in the mechanism of potentiation of neuroleptic induced catalepsy by PGs, and that PGs are similar to neuroleptics in some aspects of central action.