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Much progress has taken place in knowledge of actions and use of opioids in pain in the last quarter century. There would be much less unnecessary pain and suffering if this knowledge would be applied properly in clinical practice. Why is it not? The major reasons appear to be ignorance, false prejudices (myths) and exaggerated limitations in availability of opioids for medical treatment of pain. Even the strongest opioid analgesics do not need to relieve pain in everybody. Their effect should be monitored and if inadequate, proper measures should be taken (e.g. adjusting a dose or changing an opioid). Weak opioids (codeine, tramadol) alone are mostly not stronger then non-opioid analgesics. However, combinations of opioid analgesics with paracetamol often show synergistic analgesic effect (without increased toxicity). Opioids actually represent very safe analgesics. Exaggerated opiophobia is a major myth causing much unnecessary pain and suffering in patients. Undue fear of drug abuse and/or political considerations have resulted in laws and regulations, that make it unnecessarily difficult to obtain opioids for medical use. An example of this might be a recent re-scheduling of buprenorphine in the Czech Republic and Slovakia among drugs with a very high abuse potential (e.g. morphine, fentanyl, amphetamine).

Rationale: Flumazenil, a competitive antagonist of benzodiazepine receptors (BZRs), has been used as a probe to detect effects of putative endogenous ligands for BZRs in anxiety. Flumazenil is renowned for its highly inconsistent behavioral effects., Objective: To ascertain effects of flumazenil in the social conflict test in mice, which provides complex measures for prediction of anxiolytic and anxiogenic activity of drugs in behaviorally different groups of animals., Methods: Singly housed male mice treated with flumazenil (5, 20 or 80 mg/kg i.p.) or vehicle were paired with untreated non-aggressive group-housed male mice in a novel cage. Behavior was analyzed from video tapes of the social interactions in three populations of mice: timid (n=21), aggressive (n=11), and sociable (n=7). Levels of gamma-aminobutyric acid (GABA) were measured in vivo in the prefrontal cortex., Results: Flumazenil reduced timid (defensive-escape) and increased locomotor activities in timid mice. The drug reduced aggressive and increased sociable (social investigation) activities in aggressive mice. These behavioral changes were produced at the lowest dose of flumazenil tested (5 mg/kg) and were not increased further by higher doses of the drug (20 mg/kg or 80 mg/kg). A tendency to increased timidity was found after flumazenil in sociable mice. Concentrations of GABA were markedly higher in the prefrontal cortex of sociable mice than in timid or aggressive mice., Conclusions: Flumazenil produced moderate anxiolytic-like behavioural changes and a slight anxiogenic-like effect. The present data might be reflecting antagonism of corresponding endogenous BZR ligands. However, these putative ligands seem to exert only modest modulatory influence.

As a consequence of enhanced production of oxygen free radicals, lipid peroxidation leads to the degradation of membrane lipids and disturbances of membrane permeability. Lipid peroxidation increases under stress conditions such as hypoxia, ischemia or acidosis as well as in metabolic diseases, e.g. diabetes mellitus. We have shown that subcomatous doses of insulin (6.0 IU/kg) significantly increase thiobarbituric acid reactive substances (TBARs), especially malondialdehyde (MDA) - the endproduct of lipid peroxidation, in the brain and heart of mice. In our model of insulin-induced hypoglycemia, mice were treated with the neuroprotective, peptide-containing drug Cerebrolysin (100 mg/kg b.w.). Animals were sacrificed by decapitation two or three hours after the injection of tested substance and samples were taken to determine several serum parameters (glucose, total protein, triglycerides and lactic acid) and TBARs in the brain and heart. Although Cerebrolysin was not able to affect serum parameters after subcomatous insulin injection, the drug significantly influenced lipid peroxidation. A single injection of Cerebrolysin already decreased TBARs levels in the brain and heart tissue. Presuming that an increase of TBARs reflects disturbances of the cell membrane, we have documented a promising effect of Cerebrolysin on cell integrity.

Malondialdehyde (MDA), Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and selenium-dependent glutathione peroxidase (GSPHx) are currently considered to be basic markers of oxidative stress. MDA is one of the end-products of the peroxidation of membrane lipids, whereas enzymes Cu,Zn-SOD and GSHPx belong to the natural antioxidants. The role of oxygen free radicals in the pathogenesis of many diseases is well documented. The aim of this study was to ascertain the influence of insulin-induced acute hypoglycemia on oxidative stress in the brain tissue. Hypoglycemia was induced in ICR mice by intraperitoneal administration of insulin at a dose 24 IU/kg. There was a correlation between the severity of hypoglycemia and the levels of MDA, Cu,Zn-SOD and GSHPx. The results showed that in severe hypoglycemia (serum glucose concentration below 1.0 mmol/l) the lipoperoxidation in brain tissue expressed as the level of MDA was higher in comparison with normoglycemic controls (glycemia around 3.7 mmol/l) as well as in comparison with the levels of MDA during moderate hypoglycemia (glycemia ranging between 1-2 mmol/l). This indicates the enhancement of lipoperoxidation in the brain tissue during severe hypoglycemia. However, both enzymes - Cu,Zn-SOD or GSHPx - did not show a similar tendency.

Aim of Investigation: Guaifenesin is used as an expectorant and it has been reported to possess muscle relaxant and sedative activity. Guaifenesin has been used as a component of composite OTC analgesics containing paracetamol for many years. The aim of our study was to ascertain effects of guaifenesin on paracetamol analgesic activity and locomotor performance., Methods: Antinociceptive efficacy was tested in mice using an acetic acid (0.7%) writhing test. Locomotor performance was tested in rota-rod test and activity cage. All drugs were given orally and tested in mice., Results: In combination with a subeffective dose of guaifenesin (200 mg/kg), the ED(50) for paracetamol in the writhing test was significantly lower (82.2 mg/kg) than that of paracetamol administered alone (233.7 mg/kg). Guaifenesin alone did not show an analgesic effect. Guaifenesin did not produce statistically significant locomotor impairment in the rota-rod test at doses enhancing analgesic activity of paracetamol, although there was a trend for decreased locomotor activity in activity cage., Conclusion: The present results indicate that guaifenesin may enhance analgesic activity of paracetamol.

Objective: To determine the patterns of consumption in calcium channel blockers (CCB) groups in the Czech Republic between 1992 and 1999 and make a comparison with selected countries., Methods: This was part of a drug utilization study using WHO methodology [Anatomical Therapeutic Chemical classification/defined daily doses (ATC/DDD)]. The wholesale data collected by drug distributors were used. Utilization was calculated as the DDDs for 1000 inhabitants per day. In focus was the consumption of short-acting nifedipine. Comparison with wholesale data from Finland, Norway, Germany and Australia was made., Results: There was a decreasing tendency to use short-acting nifedipine in the Czech Republic over the period 1993-1999. Four years after publication of warning evidence, short-acting nifedipine still accounted for 23% of all calcium channel blockers in our country. The abundance of second-generation CCBs increased from less than 1% in 1993 to 43% in 1999. The consumption of short-acting nifedipine in the Czech Republic and Germany is probably three times more frequent than in Nordic countries and Australia., Conclusions: Consumption of short-acting nifedipine in the Czech Republic 4 years after recognition of its risks still remains very high. This suggests that implementation of clinical trial results to clinical practice is very slow and ineffective.

The reports of analgesic effects of benzodiazepines are inconsistent. There is evidence of a hyperalgesic effect induced by activation of supraspinal GABAA receptors and an antinociceptive effect induced by activation of receptors located in the spinal cord (dorsal horns). The aim of the study was to discover whether the systemic administration of a benzodiazepine agent alprazolam increases the systemic analgesic efficacy of non-opioid analgesic ibuprofen. Experimental studies combining these agents have not yet been published. We used three experimental methods - writhing test (with acetic acid), tail-flick test and plantar test to assess analgesic action. The drugs were administered orally. Augmentation of the analgesic effect of ibuprofen by alprazolam was proved for the writhing test at a dose of 30 mg/kg of ibuprofen and alprazolam 1 mg/kg. The reaction time of the combination was significantly prolonged in comparison with ibuprofen alone. The results of the tail-flick test and plantar test were negative. The effect of ibuprofen was not enhanced by alprazolam in tests of acute thermal pain. Our results have demonstrated that the analgesic action of ibuprofen is only weakly enhanced by alprazolam.

Benzodiazepines seem to be frequently abused in conjunction with opioids. Fluoxetine was reported to block morphine locomotor sensitization in rats. Sensitization has been implicated in some aspects of drug abuse. We have investigated the effect of alprazolam (0.25 mg/kg) and fluoxetine (5 mg/kg) on the development and expression of sensitization to the locomotor stimulant effect of morphine (10 mg/kg) in mice. Sensitization was produced by daily injections of morphine (10 mg/kg) for 10 days. There was a clear sensitization of locomotor activity produced by morphine in photocell activity cages but co-administration of alprazolam with morphine had no effect on the degree of sensitization. Alprazolam was also without effect on the expression of the sensitized response to morphine in mice sensitized with morphine alone. Fluoxetine partly reduced both the development and expression of morphine sensitization. In conclusion, the present experiments have not yielded evidence that alprazolam may influence the development or the expression of sensitization to morphine. However, they have corroborated and extended results indicating that fluoxetine can attenuate, to a certain level, the development and expression of morphine sensitization.

Rationale: It is difficult to assess withdrawal from benzodiazepines, and preclinical assessment of behaviour during social conflict offers the opportunity to quantify tolerance and withdrawal by measuring aggressive, defensive and social behaviour. The relationship between benzodiazepine withdrawal symptoms and the development of tolerance is not well understood. Are withdrawal symptoms dependent on the development of tolerance?, Objective: The aim of the present study was to compare the development of tolerance to alprazolam effects on the behavioural repertoire during the social conflict test in mice, and to determine whether or not behavioural changes during alprazolam withdrawal are correlated with the development of tolerance., Methods: An experimental model consisting of interactions of pairs of singly housed male mice with non-aggressive group-housed male mice was used. Alprazolam (1 mg/kg) was given orally once or repeatedly (twice daily) for 8 or 21 days. Behaviour was measured, based on videoanalysis, in aggressive mice before treatment, 30 min or 3 days after the last dose, respectively., Results: A single administration of alprazolam significantly reduced aggressive activities and increased social investigation without changing locomotion or other behaviour. Tolerance developed to the inhibitory effects of alprazolam on aggressive behaviour but not to the effects of alprazolam to increase social investigation. When withdrawn from alprazolam, mice exhibited less social investigation and locomotion while aggression tended to be increased., Conclusions: Tolerance to the alprazolam effects on aggressive and social behaviour developed at different rates suggesting that they are differentially regulated. Furthermore, the evidence of withdrawal responses appearing in a behaviour to which tolerance had not developed does suggest that tolerance and withdrawal phenomena are dissociated in benzodiazepines.

The most cited articles of 100 Czech pharmacologists were determined by analysis of data given in the Science Citation Index in "Web of Science". Ten most cited articles were selected according to the total number of citations till October 2000, the total number of citations during 1980-2000 and the number of citations per year during 1980-2000. The most cited articles found by this analysis represent well the significant part of research orientation of Czech pharmacologists and their major scientific contributions during the 1960s-1990s. Problems with application of citation-analysis to evaluation of research are discussed.

3alpha-Hydroxy-20-oxo-5alpha-pregnan-21-yl hemisuccinate (8) was produced by partial acylation of 3alpha,21-dihydroxy-5alpha-pregnan-20-one (14). 3alpha-Fluoro-5alpha-pregnan-20-one (9) was prepared by treatment of 3beta-hydroxy-5alpha-pregnan-20-one (11) with DAST and by solvolysis of tosylate 12 with tetrabutylammonium fluoride. A behavioral test on mice was performed using 3alpha-hydroxy-5alpha-pregnan-20-one (1) and compounds 8 and 9. Compound 8 was found to be inactive, while the fluoro derivative 9 selectively reduced aggressive behavior in mice more than the corresponding 3alpha-hydroxy compound 1; locomotion and other behavioral features were not affected.

Agroclavine is a natural, clavine type of ergot alkaloid with D1 dopamine and a-adrenoceptor agonistic properties. We showed previously that in vitro agroclavine enhances natural killer (NK) cell activity, increases interleukin-2 and interferon-gamma production and prolongs the survival time of tumor-bearing mice. The aim of this study was 1) to test the effect of agroclavine on NK activity in vivo, and 2) to assess the potential toxicity of high doses of agroclavine on cardiac and liver functions using creatine kinase MB (CKMB) and alanine aminotransferase (ALT) as biochemical markers in normal and stressed animals. The effect of stress was studied because we examined promising anticancer properties of agroclavine and malignant diseases are supposed to be a potent stressful event for patients. In our experiments 3-month-old male rats of the Wistar-Kyoto strain were used. Agroclavine was injected intraperitoneally (0.5 mg/kg or 0.05 mg/kg) 30 min before stress (four hours' restraint and immersion in 23 degrees C water). The animals were killed 30 min after stress, blood was collected and the spleen was removed. Non-stressed animals treated with agroclavine were killed 5 h after the drug administration. The results confirmed our previous in vitro results and showed that also in vivo agroclavine increases NK cell activity under non-stress conditions. Agroclavine only slightly increased CKMB and had no influence on ALT in non-stressed animals. These promising results are limited by the fact that agroclavine (0.5 mg/kg) diminished NK cell activity and significantly increased ALT and CKMB under stress conditions.

Previously, only in vitro studies have shown that chronic administration of morphine provokes long-lasting enhanced activity of accumbal cholinergic neurons, which may contribute to the behavioural sensitization, positive reinforcement and aversive effects associated with enhanced drug-seeking. The present study was aimed at clarifying whether these adaptive changes would also be supported by in vivo microdialysis measurements in freely moving rats, distinguishing between the accumbal substructures shell and core, and observing behavioural changes simultaneously. Acute administration of morphine dose-dependently decreased acetylcholine (ACh) release in the nucleus accumbens (NAc), with 10 mg/kg s.c. being most effective, 5 mg/kg ineffective. On day 5 of spontaneous abstinence from chronic morphine treatment (10-40 mg/kg morphine dose once daily for 5 days), when withdrawal symptoms were still present, even a lower morphine dose (5 mg/kg) was effective in decreasing ACh release in the NAc. During the later phase of abstinence, when no withdrawal symptoms were detectable, the opposite effect, i.e. an increase of ACh release was found. This later effect may represent a long-lasting neuroadaptive effect of morphine. These adaptive effects seemed to be more prominent in the NAc shell. Concurrent with these changes in ACh release, morphine challenges produced marked behavioural stereotypes, possibly indicating behavioural sensitization.

The analgesic effects of intracerebroventricularly (i.c.v.) administered dynorphin A(1-13) and its analog dynorphin A(1-10)amide using the hot plate test were studied in mice. Both dynorphins applied i.c.v. by the freehand method had an analgesic effect but no effect was seen when applied i.c.v. through an implanted cannula. Moreover, freehand i.c.v. injection of saline increased the time of immobility in the forced swimming test and glycaemia levels compared with intact mice. In contrast to the freehand injection, saline administration through an implanted cannula did not influence the immobility of animals in forced swimming test when compared with the intact controls. These results suggest that 1) the freehand method is very stressful procedure of administration which could influence the effects of dynorphins in the hot plate test and 2) dynorphins exert an analgesic effect in the hot plate test only when combined with a stressor (freehand i.c.v. injection).

Behavioral pattern was studied in two inbred strains of rats which have different responses to stress. These strains were originally developed from a randomly bred Wistar rat colony, according to high or low myocardial cells sensitivity to cardiotoxic effect of isoprenaline. One strain is very sensitive to isoprenaline cardiotoxicity (IS = isoprenaline sensitive) the other strain is more resistant (IR = isoprenaline resistant). In the IR strain the immobilization immersion stress causes high incidence of gastric ulcers, while the IS strain is prone to heart pathology. In this communication we report the differences in behavior of these two rat lines in three tests: open field, intruder's test and Porsolt's forced swimming test. The IS animals were passive and anxious in open field test, submissive in intruders test and they showed more floating time in Porsolt's forced swimming test. The IR rats were active, aggressive and dominant.

Dynorphin A (1-13) and its analog dynorphin A (1-10) amide were applied intracerebroventricularly in male ICR mice. Both dynorphins did not reveal any analgesic activity in tail-flick test under normal (non-stressed) conditions. However, in combination with stress (forced swimming or whole body vibration) both dynorphins prolonged tail-flick latencies when compared with stressed saline controls. Naloxone inhibited the effect of dynorphins in forced swimming test. Neither dynorphin A (1-13) nor dynorphin A (1-10) amide increased tail-flick latencies when combined with weak immobilization stress. Our results suggest that the analgesic effects of dynorphins are potentiated by strong stressors.

The effects were ascertained of two partial inverse agonists at benzodiazepine receptors (beta-CCE and FG 7142) on the incidence of timid (defensive-escape), aggressive, sociable and locomotor activities in both timid and aggressive singly-housed male mice, treated with drugs in paired interactions with untreated non-aggressive males. FG 7142 (5 mg/kg) and beta-CCE (8 mg/kg) increased defenses and escapes without producing other behavioral changes in timid mice. FG 7142 (20 mg/kg) and beta-CCE (1-8 mg/kg) moderately increased defenses and alert postures in aggressive mice and this effect was associated with marked reduction of aggressive behavior. FG 7142 (20 and 80 mg/kg) also decreased walking across cage in aggressive mice. It is concluded that beta-CCE and FG 7142 produced behavioral changes which could be interpreted as "anxiogenic".

Ethopharmacology can be defined as the study of behavioral and other effects of drugs through the use of ethological concepts. The study of drug effects on natural action patterns (motor acts and postures listed in ethograms), with respect to natural settings and to behavior as a whole (all identifiable behaviors occurring during the measurement) represents the basic concepts of ethopharmacology. Although pioneers drew attention to the potential of the ethological approach in pharmacology in the early 1960s, the number of publications utilizing this approach has steadily grown only since the mid-1970s. In the 1980s, modern technology, such as videorecorders, microcomputers and software, has been more widely applied in ethopharmacological experiments, greatly facilitating the observation and quantitative analysis of multiple data. Ethopharmacology is not "another" behavioral pharmacology, but an integral part of it. Rather, it represents one of the tools which can be useful (and sometimes even indispensable) in achieving a better understanding of the behavioral effects of drugs. It is to be hoped that it will be used in concert with other approaches in the future.

The effects of ethanol (0.4, 0.8, 1.6, and 2.4 g/kg p.o.) on behavior of aggressive, timid, and sociable male mice treated with the drug on paired interactions with non-aggressive males given water were investigated. Under control interactions, aggressive mice attacked their partners, timid mice showed defensive-escape activities though their partners were completely non-aggressive, and sociable mice intensively investigated their partners. A low dose of ethanol (0.4 g/kg) increased while higher doses (0.8 to 2.4 g/kg) reduced aggressive activities in aggressive mice. Ethanol (0.8 g/kg) also evoked aggressive behavior in non-aggressive timid mice but no dose of ethanol stimulated aggression in non-aggressive sociable mice. Ethanol altered timid defensive-escape activities only in the highest dose of 2.4 g/kg: this dose increased defences and escapes in aggressive males while it reduced defensive upright postures in timid mice. However, 2.4 g/kg of ethanol reduced also another upright movement (exploratory rearing) in timid mice. Sociable activities were not increased by any dose of ethanol tested. By contrast, 0.4 g/kg of ethanol reduced sniffing and following partners in sociable mice. Thus, ethanol exhibit relatively strong aggression-stimulating effects in aversively disposed subjects while the drug was not able to supress timid defensive escape behavior and to stimulate active non-aggressive contacts between strange male mice.

1 About 45% of singly-housed male mice showed timidity (alert postures, running away, defensive postures) instead of aggression on interactions in pairs with group-housed male mice, though their partners did not show any aggression. The isolation-induced timidity was stable in repeated interactions. Timid mice also showed locomotion (walking across cage and rearing) and a small amount of sociable activity (sniffing, following partners and climbing over them). 2 Diazepam (5 mg/kg), chlordiazepoxide (20 mg/kg), chlorpromazine (7.5 mg/kg) and barbitone (60 mg/kg) given orally inhibited the isolation-induced timidity without reducing other motor activities in the timid mice. Imipramine lessened timidith only in a dose (80 mg/kg) which also decreased other components of behaviour in the timid isolates. (+)-Amphetamine and lysergic acid diethylamide (LSD) increased the timid response. 3 Comparison of the inhibition of timid activities with changes in other behaviour occurring at the same time seems a better measure of selective timidity-reducing effects of drugs than the rota-rod test. 4 Diazepam (5 mg/kg) increased sociable and locomotor activities. Barbitone (20 and 60 mg/kg) increased sociable activities; however, the higher dose also evoked some aggression in timid mice. 5 Behaviour of timid singly housed male mice seems to be a good measure for prediction of activity of drugs in relieving anxiety as well as for detection of aggression-evoking and sociability-increasing effects of drugs.

Majority of adult male albino random-bred mice housed singly or in small groups show agonistic behavior on interaction with a strange male mouse: some of them are predominantly aggressive ('aggressive' mice) while others show defenses or escapes even though their partners are not aggressive ('timid' mice). The remaining males not exhibiting agonistic behavior ('sociable' mice) show more social investigation then aggressive or timid mice and more locomotion then timid mice. Active defensive-escape behavior ('timidity') and inhibition of social investigation and of locomotion is much stronger in an unfamiliar cage with a strange male than in a home cage or on interaction with a female. Effects of 50 drugs on behavior of aggressive and timid male mice on agonistic interactions with non-aggressive male mice in neutral cages were tested. Most of the drugs possessing anxiolytic activity in man reduced active escapes or defenses at doses lower than those inhibiting attacks or locomotion and increased social investigation while most drugs without anxiolytic activity did not show these effects. Some anxiolytic drugs reduced tail-rattling (an ambivalent activity presumably reflecting both attack and escape tendency) at doses lower than those reducing attacks and increased locomotion. Only some benzodiazepines (nitrazepam, oxazepam and diazepam) produced the whole spectrum of these effects indicating a reduced defensive-escape tendency. The present results suggest that a selective inhibition of defensive-escape tendency on agonistic interactions can be a good predictor of anxiolytic activity of drugs. Profiles of effects of seven benzodiazepines in the present model of agonistic interaction to some extent differed: triazolam, clonazepam and flunitrazepam were more sedating (reduced timidity only at doses inhibiting locomotion) while nitrazepam, oxazepam, diazepam and chlordiazepoxide were less sedating (reduced timidity at non-sedative doses, stimulated social investigation and locomotion). Only drugs stimulating GABA-receptor complex (benzodiazepines, barbiturates and GABAergic drugs) inhibited active escapes and defenses at doses lower than those reducing attacks. This suggests that the GABA-receptor complex is involved in regulation of defensive-escape tendency in intraspecies conflict.