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At least 1,765 records · Page 98Linked to original sources
PubMed2000

Effects of the cannabinoid CB(1) receptor antagonist, SR141716A, after Delta(9)-tetrahydrocannabinol withdrawal.

Rats were trained to lever press according to variable interval 10 s schedules during daily experimental sessions composed of six 3 min food reinforcement periods and were treated twice daily for 6 days with either vehicle or escalating regimens of Delta(9)-tetrahydrocannabinol. On days 7 and 8, the rats were challenged with vehicle and cumulative doses of SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4, -dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide hydrochloride), a cannabinoid CB(1) receptor antagonist, up to 3 and 9 mg/kg, respectively. Response rates increased during Delta(9)-tetrahydrocannabinol withdrawal and towards those of the vehicle treatment group suggesting a waning of the direct effects of Delta(9)-tetrahydrocannabinol. SR141716A reduced response rates but only in rats pre-treated with Delta(9)-tetrahydrocannabinol. These data suggest that dependence upon Delta(9)-tetrahydrocannabinol was induced and SR141716A precipitated withdrawal.

Animals↗
PubMed2001

The spinal antinociceptive effect of FR140423 in mice involvement of the descending noradrenergic and serotonergic systems.

In this study, we investigated the role of descending monoaminergic systems in the antinociceptive activity of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methyl sulfinyl)phenyl]pyrazole, by using the tail-pinch test in mice and various monoamine depletors. The antinociceptive effects of FR140423 given p.o. and i.t. with ED50 values of 22 mg/kg and 3.5 microg/mouse, respectively, in the tail-pinch test were antagonized by reserpine, 6-hydroxydopamine plus nomifensine, and p-chlorophenylalanine treatment, whereas the antinociceptive action of morphine in this assay was attenuated by reserpine and 6-hydroxydopamine plus nomifensine but not by p-chlorophenylalanine treatment. These results suggest that both descending noradrenergic and serotonergic systems are involved in the antinociceptive activity of spinally and systemically administered FR140423 against mechanical noxious stimuli. The mechanisms underlying the suppressive action of FR140423 on the nociceptive response may differ from those of morphine in mice.

Analgesics↗
PubMed2002

Cytochrome P450 2E1 dependent catalytic activity and lipid peroxidation in rat blood lymphocytes.

To investigate the similarities in the catalytic activity of blood lymphocyte P450 2E1 in blood lymphocyte with the liver isoenzyme, NADPH dependent lipid peroxidation and activity of N-nitrosodimethyamine demethylase (NDMA-d) was studied in rat blood lymphocytes. Blood lymphocytes were found to catalyse NADPH dependent (basal) lipid peroxidation and demethylation of N-nitrosodimethylamine (NDMA). Pretreatment with ethanol or pyrazole or acetone resulted in significant increase in the NADPH dependent lipid peroxidation and the activity of NDMA-d in blood lymphocytes and liver microsomes. In vitro addition of CCl(4) to the blood lymphocytes isolated from control or ethanol pretreated rats resulted in an increase in the NADPH dependent lipid peroxidation. Significant inhibition of the basal and CCl(4) supported NADPH dependent lipid peroxidation and NDMA-d activity in blood lymphocytes isolated from control or ethanol pretreated rats by dimethyl formamide or dimethyl sulfoxide or hexane, solvents known to inhibit P450 2E1 catalysed reactions in liver and anti- P450 2E1, have indicated the role of P450 2E1 in the NADPH dependent lipid peroxidation in rat blood lymphocytes. The data indicating similarities in the NADPH dependent lipid peroxidation and NDMA-d activity in blood lymphocyte with the liver microsome have provided evidence that blood lymphocyte P450 2E1 could be used as a surrogate to monitor and predict hepatic levels of the enzyme.

Acetone↗
PubMed2002

Singlet oxygen trapping by DRD156 in micellar solutions.

Recently, 4.4'-bis(1-p-carboxyphenyl-3-methyl-5-dydroxyl)-pyrazol (DRD156) has been developed as a new sensitive reagent that reacts specifically with singlet oxygen. The specificity of DRD156 for singlet oxygen in a biomimetic solution (micellar solution) and the effects of its coexistence with other reagent were examined with electron spin resonance (ESR). Singlet oxygen was generated using photosensitization reaction. The ESR spectrum of the radical derived from DRD156 after the reaction with singlet oxygen in phosphate buffered salines (PBS) was comprised of twenty-nine lines, whereas that in cetyltrimethylammonium bromide (CTAB) micelles was comprised of nine lines. Both 2,2,6,6-tetramethyl-4-piperidine (TMPD) and 1,3-diphenyl-isobenzofuran (DPBF) reduced the singlet oxygen-DRD156 signal intensity, and TMPD-mediated decrease in PBS (to 62%) was almost the same as that in CTAB micelle (to 65%). In contrast, DPBF reduced the DRD156 signal intensity more effectively in CTAB micelle (to 12%) than PBS (to 38%). These results indicate that the specificity of DRD156 for singlet oxygen is dependent on microenvironment.

Benzofurans↗
PubMed2001

The novel analgesic, cizolirtine, inhibits the spinal release of substance P and CGRP in rats.

Although previous studies have established that cizolirtine (5-([(N,N-dimethylaminoethoxy)phenyl]methyl)-1-methyl-1H-pyrazol citrate) is a potent analgesic in rodents, its mechanism(s) of action remain(s) unclear. In vitro and in vivo approaches were used to assess whether cizolirtine could affect the spinal release of two pain-related neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP), in rats. Cizolirtine significantly reduced the K(+)-evoked overflow of both the SP-like material (SPLM; -25% at 0.1 microM--0.1 mM) and CGRPLM (-20% at 0.1--1.0 microM) from slices of the dorsal half of the lumbar enlargement of the spinal cord. Intrathecal perfusion in halothane-anaesthetized rats showed that local application of cizolirtine markedly diminished the spinal outflow of SPLM (up to -50% at 0.1 mM) but only marginally that of CGRPLM. Systemic administration of cizolirtine at an analgesic dose (80 mg/kg i.p.) also reduced spinal SPLM outflow (-50%) but not that of CGRPLM. Under both in vitro and in vivo conditions, idazoxan (10 microM) antagonized the effects of cizolirtine on SPLM and CGRPLM release, suggesting their mediation through alpha(2) adrenoceptors.

Acetic Acid↗
PubMed2001

Anti-inflammatory activity of a novel selective cyclooxygenase-2 inhibitor, FR140423, on type II collagen-induced arthritis in Lewis rats.

The mechanism of action of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)-phenyl]pyrazole), a novel and selective cyclooxygenase (COX)-2 inhibitor, in rat type II collagen-induced arthritis was investigated and compared with that of indomethacin. We tested the inhibitory effects of FR140423 on paw edema and the formation of arachidonic acid metabolites in inflamed paws immunized with type II collagen. Oral administration of FR 140423 showed a dose-dependent anti-inflammatory effect and was two-fold more potent than indomethacin. The increase of prostaglandin (PG) E2 and thromboxane (TX) B2 but not leukotriene B4 in inflamed paws was associated with the development of paw edema. FR140423 and indomethacin dose-dependently suppressed the levels of PGE2 and TXB2 in arthritic rat paws. Unlike indomethacin, FR140423 did not induce gastric lesions in arthritic rats. These results suggest that FR140423 shows a potent anti-inflammatory effect mediated by inhibition of prostanoids produced by COX-2 in inflamed tissues immunized with type II collagen, with a greatly improved safety profile compared to indomethacin.

Animals↗
PubMed2001

3-Methyl-5-hydroxy-5-trichloromethyl-1H-1-pyrazolcarboxyamide induces antinociception.

The antinociceptive action of a novel pyrazole-derived compound, 3-methyl-5-hydroxy-5-trichloromethyl-1H-1-pyrazolcarboxyamide (MPCA) was evaluated using the formalin and tail-immersion tests in mice. Anti-inflammatory activity was assessed by paw plethysmometry in adult rats using the carrageenin-induced paw edema test. Subcutaneous administration of MPCA (22, 66, and 200 mg/kg) induced a dose-dependent decrease in the time spent licking during the neurogenic and inflammatory phases of the formalin test, and preadministration of naloxone (1 mg/kg, sc) did not prevent MPCA-induced (200 mg/kg, sc) antinociception. Naloxone decreased the spontaneous locomotor activity of mice, while MPCA had no effect on locomotion. In contrast, administration of the opioid antagonist caused a significant increase in the locomotor behavior of mice previously injected with MPCA. MPCA was devoid of antinociceptive action by the tail-immersion test and of anti-inflammatory activity. Moreover, MPCA had no effect on the motor performance of mice in the rotarod test. These results suggest that MPCA induces antinociception in the neurogenic and inflammatory phases of the formalin test, an effect that does not involve opioid receptors.

Analgesics↗
PubMedDate not supplied

Reversal of delta 9-THC hyperphagia by SR141716 and naloxone but not dexfenfluramine.

Presatiated adult male Lister hooded rats received oral administration of the exogenous cannabinoid Delta-9-tetrahydrocannabinol (Delta(9)-THC; 1.0 mg/kg) in combination with subcutaneous injection of either the cannabinoid CB1 antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716; 0, 0.05, 0.1, 0.5 or 1.0 mg/kg), the CB2 antagonist N-[(1S)-endo-1,3,3-trimethyl bicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 0, 0.05, 0.1, 0.5 or 1.0 mg/kg), the general opioid antagonist naloxone (0.1, 0.5, 1.0 or 5.0 mg/kg) or the 5-HT agonist dexfenfluramine (0.05, 0.1, 0.5, 1.0 or 5.0 mg/kg). Food (chow) intake was measured over 2 h from the onset of the dark period. Delta(9)-THC induced significant hyperphagia, which was attenuated by subanorectic doses of SR141716 and naloxone. Neither SR144528 nor dexfenfluramine affected Delta(9)-THC-induced feeding. These data confirm mediation of Delta(9)-THC hyperphagia by central-type CB1 receptors, and support a functional relationship between cannabinoid and opioid systems in relation to appetite regulation. Stimulation of CB1 receptors may promote feeding by actions on food reward rather than by inhibition of serotonergic satiety mechanisms.

Animals↗
PubMed2002

Tolerance to the disruptive effects of Delta(9)-THC on learning in rats.

Tolerance to the effects of the cannabinoid agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was characterized in rats responding under a multiple schedule of repeated acquisition and performance. During the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component the sequence was the same each session. Responding was maintained under a second-order fixed-ratio 2 (FR2) schedule of food reinforcement. Acute doses of Delta(9)-THC (1-10 mg/kg) decreased rate and accuracy in both components, whereas doses of the cannabinoid (CB1) receptor antagonist N-(piperidin-1-yn-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; 0.32 and 1 mg/kg) were ineffective. While 5.6 mg/kg of Delta(9)-THC disrupted responding when administered acutely, tolerance to the rate-decreasing and error-increasing effects of this dose developed in both components after daily administration. When 1 mg/kg of SR141716A was substituted for Delta(9)-THC during chronic administration, this previously ineffective dose selectively increased within-session errors in the acquisition component of the multiple schedule. During the postchronic phase, subjects were generally less sensitive to the disruptive effects of Delta(9)-THC. In summary, these data demonstrated that tolerance to Delta(9)-THC developed across two different behavioral tasks and that learning was generally more sensitive than performance to the effects of SR141716A during chronic treatment with Delta(9)-THC.

Animals↗
PubMed2003

The Cu(II) acetate complex of the heteroscorpionate ligand (2-hydroxy-3-t-butyl-methylphenyl)bis(3,5-dimethylpyrazolyl)methane: a structural model for copper-substituted serralysin and astacin.

Reaction of Cu(II) acetate with the deprotonated ligand (2-hydroxy-3-t-butyl-methylphenyl)bis(3,5-dimethylpyrazolyl)methane (L1O(-)) in methanol produced the complexes [(L1O)Cu(OAc)], a=9.275(2), b=11.641(5), c=13.532(3) A, alpha=69.62(1) degrees, beta=89.49(2) degrees, gamma=87.12(1) degrees, P1. The Cu adopts a distorted five-coordinate geometry where the two pyrazole nitrogen ligands and a bidentate acetate occupy the pseudoequatorial plane with the phenoxy oxygen in an apical position. This complex has a number of features in common with galactose oxidase and the copper-substituted endopeptidases serralysin and astacin.

Crystallography, X-Ray↗
PubMed2002

Developmental toxicity of flupyrazofos, a new organophosphorus insecticide, in rats.

Flupyrazofos is a new type of pyrazole organophosporus insecticide, which has a high activity against the diamond-back moth (Plutella xylostella). The potential of this agent to induce developmental toxicity was investigated in the Sprague-Dawley rat. One hundred mated females (sperm in vaginal LAVAGE=day 0) were distributed among three treated groups and a control group. Flupyrazofos was administered by gavage to pregnant rats from days 7-17 of gestation at dose levels of 0, 5, 12 and 30 mg/kg/day. All dams were subjected to the caesarean section on day 20 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. At 30 mg/kg, maternal effects including mortality (4.3%), clinical signs of toxicity, decreased food intake, suppressed body weight, and increased weight of adrenal glands, kidney and heart were observed in dams. Litter values for corpora lutea, implantations, sex ratio and litter size were within the normal range. However, a reduction in the fetal weight and an increase in the incidence of fetal skeletal retardations were observed. At 12 mg/kg, toxic effects including mortality (4.2%), nasal discharge and some fetal skeletal retardation were observed. There were no signs of either maternal toxicity or embryotoxicity at 5 mg/kg. The results show that flupyrazofos induces fetal growth retardation only at maternally toxic doses in rats and the no-observed-adverse-effect levels (NOAELs) of this agent are considered to be 5 mg/kg for both dams and fetuses.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Percutaneous penetration of 2-phenoxyethanol through rat and human skin.

2-Phenoxyethanol applied in methanol was absorbed (64 +/- 4.4% at 24 hr) through unoccluded rat skin in vitro in the static diffusion cell with ethanol/water as receptor fluid. By comparison (43 +/- 3.7% in 24 hr) was absorbed in the flow-through diffusion system with tissue culture medium as receptor fluid. 2-Phenoxyethanol applied in methanol was absorbed (59.3 +/- 7.0% at 6 hr) through unoccluded human skin in vitro in the flow-through diffusion cell with tissue culture medium. With both unoccluded cells, 2-phenoxyethanol was lost by evaporation but occlusion of the static cell reduced evaporation and increased total absorption to 98.8 +/- 7.0%. Skin, post mitochondrial fraction, metabolized phenoxyethanol to phenoxyacetic acid at 5% of the rate for liver. Metabolism was inhibited by 1 mM pyrazole, suggesting involvement of alcohol dehydrogenase. However, first-pass metabolism of phenoxyethanol to phenoxyacetic acid was not detected during percutaneous penetration through viable rat skin in the flow-through system. First-pass metabolism in the skin does not therefore have an influence on systemic availability of dermally absorbed phenoxyethanol. These measures of phenoxyethanol absorption through rat and human skin in vitro agree well with those obtained previously in vivo.

Animals↗
PubMed2001

Acute exposure to trichloroethylene differentially alters the susceptibility to chemoconvulsants in mice.

The effects of a common industrial solvent, trichloroethylene (TCE), which was once used as an anesthetic agent but its in vivo mechanism is still unknown, on convulsant-induced seizures in mice were examined. Pretreatment with TCE (250-2000 mg/kg, i.p.) significantly increased pentylenetetrazol (PTZ)-, picrotoxin (PIC)-, bicuculline (BIC)-, strychnine (STY)-, 4-aminopyridine (4-AP)- and N-methyl-D-aspartate (NMDA)-induced convulsion thresholds and lethal doses. However, the increase in convulsion thresholds and lethal doses was much greater for GABAergic antagonists (PIC, BIC, and PTZ) than non-GABAergic convulsants (STY, 4AP, and NMDA) following 2000 mg/kg TCE administration. Pre-treatment of mice with disulfiram (an inhibitor of CYP 4502E1) but not 4-methyl pyrazole (an inhibitor of alcohol dehydrogenase) significantly prolonged the time required for TCE (5000 mg/kg, i.p.) to induce the loss of righting reflex. These results suggest that acute exposure to TCE differentially alters the susceptibility to chemically induced convulsions in mice. The anticonvulsive effect of TCE may be predominantly mediated by GABA(A) receptors. In addition, TCE appears to exert a direct anesthetic effect.

Animals↗
PubMed2003

Species variations in cutaneous alcohol dehydrogenases and aldehyde dehydrogenases may impact on toxicological assessments of alcohols and aldehydes.

Alcohol dehydrogenase (ADH; EC. 1.1.1.1) and aldehyde dehydrogenase (ALDH; EC 1.2.1.3) play important roles in the metabolism of both endogenous and exogenous alcohols and aldehydes. The expression and localisation patterns of ADH (1-3) and ALDH (1-3) were investigated in the skin and liver of the mouse (BALB/c and CBA/ca), rat (F344) and guinea-pig (Dunkin-Hartley), using Western blot analysis and immunohistochemistry with class-specific antisera. ALDH2 expression and localisation was also determined in human skin, while ethanol oxidation, catalysed by ADH, was investigated in the mouse, guinea-pig and human skin cytosol. Western blot analysis revealed that ADH1, ADH3, ALDH1 and ALDH2 were expressed, constitutively, in the skin and liver of the mouse, rat and guinea-pig. ADH2 was not detected in the skin of any rodent species/strain, but was present in all rodent livers. ALDH3 was expressed, constitutively, in the skin of both strains of mouse and rat, but was not detected in guinea-pig skin and was absent in all livers. Immunohistochemistry showed similar patterns of expression for ADH and ALDH in both strains of mouse, rat, guinea-pig and human skin sections, with localisation predominantly in the epidermis, sebaceous glands and hair follicles. ADH activity (apparent V(max), nmoles/mg protein/min) was higher in liver (6.02-16.67) compared to skin (0.32-1.21) and lower in human skin (0.32-0.41) compared to mouse skin (1.07-1.21). The ADH inhibitor 4-methyl pyrazole (4-MP) reduced ethanol oxidation in the skin and liver in a concentration dependent manner: activity was reduced to approximately 30-40% and approximately 2-10% of the control activity, in the skin and liver, respectively, using 1 mM 4-MP. The class-specific expression of ADH and ALDH enzymes, in the skin and liver and their variation between species, may have toxicological significance, with respect to the metabolism of endogenous and xenobiotic alcohols and aldehydes.

Adolescent↗
PubMed1979

Studies on the tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea in mice.

The tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea has been studied in mice. A large part of the injected N-[14C]ethyl-N-nitrosourea radioactivity was found to be exhaled as 14CO2. Whole-body autoradiography showed evenly distributed radioactivity in most tissues shortly after the administration of N-[14C]ethyl-N-nitrosourea which probably is due to the homogeneously distributed substance and the non-enzymatically formed ethyl-carbonium ions which have reacted with the tissues. The blood-brain barrier seemed to have a capacity to partially prevent the uptake of the substance in the central nervous system. A high radioactivity was observed in the liver, which may imply that N-[14C]ethyl-N-nitrosourea is enzymatically decomposed in this tissue. An observed labelling of kidneys may be connected with urinary excretion of radioactivity. The radioactivity in the liver and kidney decreased at later survival intervals and a distribution pattern appeared, which was characterized by a labelling of tissues with a high protein or steroid synthesis and of fat containing tissues. The distribution pattern corresponded to the one seen after the administration of [14C]acetaldehyde and is probably due to normal biosynthetic incorporation of radioactivity in the 2-carbon pool. Pretreatments with pyrazole, nialamide and diethyldithiocarbamate caused a marked inhibition of the exhalation of 14CO2 and of the incorporation of radioactivity in the liver. This effect may be directed towards the decomposition of N-[14C]ethyl-N-nitrosourea itself, but an effect on the metabolism of formed 2-carbon fragments is also possible. The incorporation of radioactivity in other tissues was not influenced by the pretreatments.

Acetaldehyde↗
PubMed1979

Inhibitors for the mutagenicities of colon carcinogens, 1,2-dimethylhydrazine and azoxymethane, in the host-mediated assay.

Inhibitory effects of several chemicals on the mutagenicities of 1,2-dimethylhydrazine (DMH) and azoxymethane (AOM) for Salmonella typhimurium G46 in the host-mediated assay were investigated. They were carbon disulfide (CS2), tetraethylthiuram disulfide (disulfiram, DSF), sodium diethyldithiocarbamate (SDDC), ethylene-bis(dithiocarbamato) manganese (Maneb), pyrazole (PZ), aminoacetonitrile hydrogen sulfate (AAN), and sodium selenite (SE). All the compounds, except for SE, inhibited the mutagenicities of DMH and AOM.

Aminoacetonitrile↗
PubMed2003

Potentiation of penile erection and yawning responses to apomorphine by cannabinoid receptor antagonist in rats.

The effect of systemic administration of the cannabinoid antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide) on penile erection and yawning induced by apomorphine was investigated in rats. SR 141716A (2 mg/kg, i.p.) administered 40 min before apomorphine (40 and 80 microg/kg, s.c.) increased the number of penile erection and yawning responses. The administration of cannabinoid agonist Delta9-tetrahydrocannabinol (1.25 mg/kg, i.p.) 15 min before apomorphine (40 and 80 microg/kg, s.c.) did not affect penile erection, however it decreased yawning. The present results provide additional evidence that cannabinoid agonists interfere with dopaminergic systems and that SR 141716A together with a dopaminergic agonist could be useful to potentiate dopaminergic activity.

Animals↗
PubMed2003

Effect of systemic FR140423, a new analgesic compound, in a rat model of postoperative pain: contribution of delta-opioid receptors.

We investigated the anti-hyperalgesic effect of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl-5-[4-(methylsulfinyl)phenyl]pyrazole, in a rat model of postoperative pain. Oral administration of FR140423 at doses between 1 and 100 mg/kg after surgery dose dependently attenuated the punctate mechanical hyperalgesia caused by an incision of the plantar surface of the hind paw with an ED50 value of 59 mg/kg. The anti-hyperalgesic effect of systematically administered FR140423 was blocked by naloxone, a non-selective opioid receptor antagonist. Furthermore, the delta-opioid receptor antagonist naltrindole (0.2 mg/kg) reversed anti-hyperalgesia induced by FR140423. Naloxonazine and nor-binaltorphimine failed to antagonize the anti-hyperalgesic effect of FR140423. The action of FR140423 differs from the naloxonazine-reversible anti-hyperalgesia induced by morphine. The present findings suggest that delta-opioid systems play a role in the rat anti-hyperalgesia produced by FR140423 for postoperative pain characterized by mechanical hyperalgesia.

Analgesics↗