Homocysteine plasma levels correlate with intimal carotid artery thickness in haemodialysis patients.
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Adult↗
Biomedical subjects
E Gori
Publications and source records attributed to E Gori.
A novel method for self-administering addicting drugs intracerebroventricularly in a free-choice procedure.
This paper describes a safe method for long term intracerebroventricular (i.c.v.) drug administration. Employing a non-preferred lever to control the self-administration the technique offers advantages over existing experimental methods. To check for any innate preference for one of two levers, male Wistar rats were allowed during the training procedure, to press two levers (L1 and L2) for one hour/day to obtain water as reinforcer for one week in a continuous reinforcement schedule (CRF). One week after surgery, during which a double-guide stainless steel cannula was inserted into both lateral ventricles, rats received 2 microliter of sterile cerebrospinal fluid (CEPH) each time they pressed one of two levers during the daily one-hour session. When a stable baseline was reached, rats were divided into three groups on the basis of their lever preference, and submitted to the testing procedure. A potent mu-opiate receptor agonist, etonitazene (0.1-0.2-1 microgram/infusion), was always associated with the non-preferred lever for each rat. When no obvious preference was shown for either lever the opiate was firstly delivered by L1(for 11 days) and then by L2 (for 20 days). The results indicate that, regardless of which lever had been preferred initially, the rats increased the pressing of only the lever associated with the opiate. The daily amount taken increased linearly and was behaviorally active. This model highlights for the first time the reinforcing properties of drugs given i.c.v. in a free-choice situation.
Analgesics, Opioid↗
Polydeoxyribonucleotide (defibrotide) protects against post-ischemic behavioral, electroencephalographic and neuronal damage in the gerbil.
The effectiveness of defibrotide, a single-stranded polydeoxyribonucleotide compound, in preventing damage caused by cerebral ischemia was studied. Global ischemia was induced in anesthetized gerbils by bilateral carotid artery occlusion for 10 min. Defibrotide (100 mg/kg) or saline was injected, i.v., immediately after reperfusion. The following parameters were evaluated simultaneously: (1) electroencephalographic (EEG) spectral power, recorded before, during and after the ischemic period; (2) body temperature, monitored with a rectal thermistor probe after reperfusion for 120 min; (3) spontaneous motility, evaluated through a photocell system and quantified in terms of total distance travelled in 30 min, 1 h after recirculation and at periods over 15 days; (4) mnemonic functions assessed by passive avoidance test from 3 to 15 days after ischemia; (5) histological examination, 7 days after reperfusion, counting CA1 hippocampal neuronal cells. The ischemia-induced complete flattening of spectral power was significantly reversed (P < 0.01) by post-ischemic treatment with defibrotide between 30 and 90 min after ischemia. A complete recovery of total EEG spectral power was seen in the defibrotide group at 6 h and the saline ischemic group at 1 day. Seven days after bilateral carotid occlusion, there was a significant decrease in spectral power (-70% +/- 6) together with a loss of the number of CA1 cells in the saline ischemic group (-64%). Treatment with defibrotide significantly protected against the decrease in spectral power (-30% +/- 7) and cell loss (-9%). Finally, the number of animals found to be protected against the ischemia-induced flattening was significantly larger for defibrotide-treated gerbils than for saline-treated animals throughout the experiment except for the third day. Body temperature was significantly decreased only at 30 min after reperfusion in both ischemic and sham-operated groups. Defibrotide reduced ischemia-induced hypermotility but only 6 h after the insult. The ischemia-induced impairment of memory was partially reversed within 3 days in the defibrotide-treated animals and fully reversed within 7 days in the defibrotide group and 15 days in the saline group. Our results demonstrate that defibrotide, even when administered after the post-ischemic period, possesses anti-ischemic properties. The mechanism by which defibrotide protects the ischemic reperfused brain is still largely unknown. However, a neuroprotection via adenosine A1 and A2 subtype receptor interaction can be put forward.
Animals↗
Naltrexone, naltrindole, and CTOP block cocaine-induced sensitization to seizures and death.
I.c.v. injection for 9 days of either naltexone (NTX) (5, 10, 20, 40 micrograms/rat) or a selective mu peptide (CTOP) (0.125, 0.25, 0.5, 1, 3, 6 micrograms/rat) or delta (naltrindole) (NLT) (5, 10, 20 micrograms/rat) subtype opioid receptor antagonist affected sensitization to cocaine (COC) (50 mg/kg, i.p.) administered 10 min after. NTX (5 and 40 micrograms/rat), NLT (10 and 20 micrograms/rat), and the peptide CTOP (0.25-0.5 microgram/rat) attenuated seizure parameters (percent of animals showing seizures, mean score and latency) in a day-related manner. The DD50 (days to reach 50% of death) value for COC was 2.69, whereas it was 9.67 and 7.27 for NTX 5 and 40 micrograms/rat, 8.59 for NLT (10 micrograms/rat), and 6.11, 5.95, and 4.30 for CTOP (0.25, 0.5, and 1 microgram/rat respectively). These findings suggest a concurrent involvement of mu- and delta-opioid receptor subtype in COC-induced sensitization to toxic effects.
Animals↗
Biochemical characterization of the effects of the benzodiazepine, midazolam, on mitochondrial electron transfer.
Midazolam, a water soluble benzodiazepine used as a preanaesthetic and hypnotic drug, showed a concentration-related (0.1-0.75 mM) depressant effect on both Adenosine 5'-diphosphate (ADP)-induced oxygen consumption and oxidative phosphorylation of rat liver mitochondria if the substrate was oxidized at different steps in the oxidation chain, but not when the substrate was ascorbate plus tetramethyl-p-phenylenediamine (complex IV). Furthermore, midazolam did not affect citrate synthase activity, but inhibited the 2,4 dinitrophenol (DNP)-uncoupled mitochondrial respiration. This result shows that midazolam primarily acts as a mitochondrial electron transport inhibitor. This inhibition is mainly due to the fact that midazolam decreases NADH ubiquinone reductase (complex I) and ubiquinol cytochrome c reductase (complex III) activities, but it also inhibits complex II activity. Spectrophotometric measurements of redox states of rat skeletal muscle mitochondria cytochromes show a decrease in the reduction of aa3 and c+c1 cytochromes in the presence of the benzodiazepine. Midazolam significantly decreased the reduced ubiquinone/total ubiquinone ratio (evaluated by means of HPLC and electrochemical detection) in rat liver mitochondria in both beta-hydroxybutyrate and succinate. Ubisemiquinone may be the redox component affected by midazolam, whether or not bound to the iron-sulfur proteins present in all three mitochondrial complexes. These effects of midazolam, not necessarily related to the preanaesthetic and hypnotic action are probably mediated via mitochondrial benzodiazepine receptors.
Animals↗
Changes in opioid receptor density on murine splenocytes induced by in vivo treatment with morphine and methadone.
In a 24-hr time course study we reported previously that a single systemic injection of morphine profoundly affected various immune parameters in mice. In the present study we examined whether these effects are mediated by changes in opioid receptor density on murine splenocytes after acute in vivo morphine (20 mg/kg s.c.) and methadone (12.5 mg/kg s.c.) at equianalgesic doses. To define the splenocyte subpopulations we used flow cytofluorimetric analysis with specific fluorescent monoclonal antibodies and calculated the binding of the fluoresceinyl opiate antagonist naloxone on opiate receptors. Both morphine and methadone reduced the density of opiate receptors on B- and T-lymphocytes. Specifically, 20 min, 1 and 3 days after the injection there was a marked reduction (about 55%) in naloxone binding sites; these returned to base line after 5 days for T-lymphocytes and after 7 days for B-lymphocytes. Despite the low proportion of macrophages among total splenocytes (about 10%), our results also indicate a tendency to a reduction in opiate receptor density also in the macrophage population. These findings indicate that a single exposure to morphine and methadone results in a strong, lasting down-regulation of opiate binding sites in murine splenocytes, probably accounting for the immunomodulation induced by opiates.
Analgesics, Opioid↗
Different kinetics of tolerance to behavioral and electroencephalographic effects of chlordiazepoxide in the rat.
The daily oral administration of chlordiazepoxide (40 mg/kg) over 9 weeks in rats elicited full tolerance to muscle relaxant effects within 7 weeks, as revealed by twice weekly evaluations of abdominal tone myorelaxation and decreased grip strength. No full tolerance was achieved, however, during the 9 weeks of treatment in terms of ataxia. Electroencephalographic (EEG) studies showed that this tolerance to the behavioural effects was accompanied by a progressive decrease in mean power spectra, associated with a progressive decrease in the beta band, but in this case, full tolerance was reached within 4 weeks. Once weekly evaluations of the ability of chlordiazepoxide to protect the animals against pentylenetetrazole seizures revealed a similar pattern. Treatment with flumazenil (50 mg/kg p.o.) 24 h after the last chlordiazepoxide administration induced a clear withdrawal syndrome associated with EEG changes which consisted of an increase in total power spectra associated with an increase in the delta band (in comparison with chlordiazepoxide-dependent rats not given the antagonist). These findings suggest that the different kinetics of the tolerance to anticonvulsant and EEG effects in comparison to myorelaxant effects can be attributed to a different involvement of benzodiazepine receptor subtypes.
Animals↗
Behavioral and biochemical evidence of opioidergic involvement in cocaine sensitization.
Chronic administration of cocaine produces sensitization to its behavioral effects in humans and experimental animals. In the present study, rats treated with cocaine (10 mg/kg, i.p.) once daily for 10 days showed an enhancement in the acute drug stimulation of locomotor activity and stereotypy. Biochemical analysis in the nucleus accumbens of chronic cocaine-treated animals indicated that sensitization of D1 dopamine (DA) receptors had also developed. In fact, stimulation of adenylyl cyclase activity by DA was increased in nucleus accumbens membranes from sensitized rats. Our findings suggest that a novel postsynaptic mechanism, i.e., an increased DA-D1 receptor function, may play a role in the sensitization. A causal relationship between the two events is supported by the observation that neither motor behavioral sensitization nor DA-dependent adenylyl cyclase hyperactivity developed when the opiate antagonist naltrexone (2 mg/kg, s.c.) was given daily for 10 days before cocaine. When given alone, naltrexone was inactive in all respects, which rules out any unspecific action and suggests that its effects may be due to competition at receptors with endogenous opioids mobilized by cocaine. This was indirectly supported by the finding that desensitization of opioid inhibition of adenylyl cyclase developed in nucleus accumbens membranes of cocaine-sensitized rats. Chronic blockade of opioid receptors by naltrexone also counteracted the reinforcing properties of cocaine; conditioned place preference, clearly displayed by cocaine-treated animals, was antagonized in a dose-related manner. Overall, these results confirm that endogenous opioid peptides play an important role in cocaine addiction.
Adenylyl Cyclases↗
Relationship between morphine and etonitazene-induced working memory impairment and analgesia.
An 8-arm radial maze task was used to assess the possible role of the opiate system in the spatial memory of the rat. Increasing doses of etonitazene (0.005-0.06 mg/kg i.p.) and morphine (2.5-100 mg/kg i.p.) significantly impaired performance in the working memory components of the task. For both drugs this impairment was linearly related to the log of the administered dose, and the log-dose relationships were parallel. The regression lines calculated for each parameter for both drugs were parallel thus allowing us to calculate the potency: etonitazene proved to about 1000 times more potent than morphine in terms of correct arm entries, the number of errors and the total time taken to complete the task. Moreover, the progressive cognitive impairment produced by both opiates was closely related to an increase in analgesic effect. Pretreatment with naloxone (5 mg/kg i.p.) completely antagonised the disruptive effect of the opiates on working memory. The importance of the mu subtype opiate receptor in cognitive processes is discussed.
Analgesia↗
Intestinal effect of morphine 6-glucuronide: in vivo and in vitro characterization.
Morphine 6-glucuronide, a major metabolite of morphine with potent analgesic actions, is a potent inhibitor of intestinal motility when administered to rats by the intracerebroventricular (i.c.v.) route. Morphine 6-glucuronide was 62-fold more active than morphine in inhibiting gastrointestinal transit, whereas it was only 25-fold more potent in abolishing intestinal migrating myoelectric complexes. Pretreatment with naloxone (5 micrograms/rat i.c.v.) completely prevented the disappearance of migrating myoelectric complexes induced by the morphine metabolite. In contrast, in the guinea pig ileum bioassay, morphine 6-glucuronide and morphine inhibited the electrically evoked contractions of the tissue with similar potency, although in the guinea pig ileum binding assay the metabolite showed 4-fold lower affinity for the opiate receptor. The low naloxone Ke values against morphine 6-glucuronide or morphine indicated that the action of both drugs in guinea pig ileum was mediated by mu-opioid receptors.
Animals↗
Effect of morphine and methadone acute treatment on immunological activity in mice: pharmacokinetic and pharmacodynamic correlates.
This report describes the 24-hr time course of the immunomodulatory effects of an acute s.c. injection of morphine in C57BL6 mice, and correlates these effects with the drug's analgesic properties and serum levels. Acute morphine treatment had a biphasic effect on various immune parameters: there was an increase in in vitro phagocytosis and the killing of Candida Albican cells by peritoneal polymorphonuclear leukocytes 20 and 40 min after the injection of morphine, 20 mg/kg, when analgesia and serum morphine concentrations were at their peak. Interestingly, 24 hr after morphine administration (when antinociception and morphine blood levels were no longer detectable) these parameters underwent a marked reduction. Similarly, macrophage-mediated inhibition of tumor cells proliferation was first stimulated (at 20 and 40 min) and then depressed (at 24 hr). Splenic natural killer cell cytotoxicity, determined by standard 51Cr release from YAC-1 target cells, also was evaluated. No differences in natural killer activity was observed at any of the monitored time points. In addition, we evaluated the immunomodulatory effects of an acute injection of methadone (a synthetic narcotic compound) at a dose inducing the same degree of analgesia as morphine. None of the tested immunoparameters were affected by the administration of methadone, which indicates the different drug-sensitivity of immunological correlates in vivo.
Animals↗
In situ hybridization reveals specific increases in G alpha s and G alpha o mRNA in discrete brain regions of morphine-tolerant rats.
In situ hybridization histochemistry has been used to detect the basal distribution of mRNA encoding the alpha subunit of Gs, Go and Gi2 proteins throughout the rat brain. Based on these data we investigated the effect of chronic morphine on the content of these G protein alpha subunits mRNA. We observed an increase in the expression of alpha s and alpha o messages of chronically morphine-treated animals, while no changes were seen in alpha i2 mRNA. Specifically a 30% increase in expression for alpha s was seen only in the paraventricular nucleus of hypothalamus and a 20% elevation for alpha o was detected in the claustrum and endopiriform nucleus. Immunoblotting analysis was used to correlate the changes in alpha s and alpha o messages with equivalent changes in protein levels. Chronic morphine significantly increased alpha s amounts in the hypothalamus (70%), and produced a minor elevation (30%) in G alpha o levels in the olfactory area. Our results indicate that in discrete brain regions altered G protein expression is part of the adaptive changes underlying opiate tolerance.
Animals↗
Influence of pertussis toxin on thermic responses to morphine and neurotensin in rats.
The influence of pertussis toxin (PTX) on thermic responses elicited by morphine and neurotensin was evaluated in unrestrained rats kept at 22 degrees C. High doses of morphine (9-36 micrograms/rat i.c.v.) lowered body temperature and low doses (1.25, 2.5 micrograms/rat i.c.v.) produced hyperthermia. The hyperthermic effect was more resistant than the hypothermic effect to naloxone antagonism. Neurotensin (50, 100 micrograms/rat i.c.v.) induced marked hypothermia followed by hyperthermia. I.c.v. injection of PTX (1 microgram), six days before morphine (18 micrograms/rat i.c.v.), replaced the opiate hypothermia by consistent hyperthermia and reduced by 60% the hyperthermia elicited by morphine (2.5 micrograms/rat i.c.v.). The toxin also affected the thermic responses induced by neurotensin (50 micrograms/rat i.c.v.) administered six days after PTX (1 microgram/rat i.c.v.). The initial hypothermia was enhanced by 173% and the late hyperthermia was fully antagonized. It thus appears that PTX-sensitive G-proteins play different roles in the molecular events underlying the thermoregulatory responses to morphine and neurotensin.
Animals↗
Influence of omega-conotoxin on morphine analgesia and withdrawal syndrome in rats.
The effect of omega-conotoxin on opiate analgesia and withdrawal syndrome was investigated in rats. omega-Conotoxin given i.c.v. and i.p. caused weak analgesia in the tail-flick test. When the toxin (20 ng/rat) was given i.c.v. immediately before morphine (1.5 micrograms/rat i.c.v.) the resultant analgesic effect was additive. In contrast, the analgesia elicited by morphine (3 micrograms/rat i.c.v.) was greatly reduced after 24-h pretreatment with the toxin (20 ng/rat i.c.v.). The systemic administration of the toxin (10 micrograms/kg i.p.) did not affect morphine analgesia whether omega-conotoxin was coadministered with morphine (2.5 mg/kg i.p.) or was given 24 h before the opiate (5 mg/kg i.p.). omega-Conotoxin i.c.v. injected in morphine-dependent rats 15 min before naloxone challenge significantly attenuated the abstinence syndrome. On the contrary systemic administration of omega-conotoxin failed to suppress the morphine withdrawal syndrome. The present results suggest that omega-conotoxin affects both acute and chronic effects of morphine.
Analgesia↗
Dose-dependent conditioned place preference produced by etonitazene and morphine.
The conditioned place preference (CPP) paradigm was used to study the reinforcing properties of etonitazene in comparison with those of morphine. Increasing doses of etonitazene (2.5-15 micrograms/kg i.p.) and morphine (1-80 mg/kg i.p.) induced a dose-dependent CPP. High doses of etonitazene (25-40 micrograms/kg) did not elicit CPP. In addition, these reinforcing properties were related to behavioral modifications such as analgesia, assessed with the tail-flick method, and increased catalepsy, evaluated by a scoring system. It is concluded that neither the strong behavioral effects induced by etonitazene nor tolerance to such effects account for the results. These findings are discussed with regard to the possibility that etonitazene could interfere with associative learning motivated by reward.
Analgesia↗
Further investigations on the antipropulsive effect of centrally administered histamine and its relation with morphine.
The effect of intracerebroventricularly (i.c.v.) administered histamine (100 micrograms/rat) on intestinal myoelectrical activity was investigated in the jejunum of fasted rats. Histamine caused the disappearance of phase III and a partial reduction of phase II of migrating myoelectric complexes. This effect was antagonized by i.c.v. pretreatment with mepyramine (10 micrograms/rat), an H1 receptor antagonist. Lesions of central noradrenergic neurons by i.c.v. injection of the neurotoxin 6-hydroxydopamine strongly reduced both the inhibition of intestinal propulsion and the migrating myoelectric complexes profile induced by i.c.v. histamine, whereas pretreatment with p-chlorophenylalanine, a selective depletor of serotonin stores, had no effect. It thus appears that aminergic pathways are involved in the visceral effects of central histamine. Mepyramine (200 micrograms/rat i.c.v.) partially reduced the slowing of intestinal transit induced by high doses of morphine. Pretreatment with compound 48/80 (10 micrograms/rat i.c.v.), a mast cell degranulator, but not with alpha-fluoromethylhistidine, an irreversible inhibitor of histidine decarboxylase, reduced the antipropulsive action of i.c.v. morphine to the same extent as mepyramine, suggesting that histamine released from cerebral mast cells by high doses of morphine could contribute to the intestinal inhibition by morphine.
Animals↗
[The appearance of a PNH clone during enzymopenic hemolytic anemia].
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Anemia, Hemolytic, Congenital↗
Effect of centrally administered atropine and pirenzepine on radial arm maze performance in the rat.
The effect of two anticholinergic drugs administered intracerebroventricularly on acquisition of an 8-arm radial maze task was examined in the rat. Increasing doses of atropine (1, 4.5, 22.5, 45 micrograms/rat) and pirenzepine (4.5, 15, 60, 90 micrograms/rat) significantly impaired performance in the working-memory components of the task. For both drugs this impairment was linearly related to the log of the administered doses and log-dose-response relationship were parallel. The regression lines calculated for each parameter for both drugs were parallel to each other, thus allowing us to calculate the potency of atropine versus pirenzepine: atropine was 5.4 times more potent than pirenzepine for correct arm entries, 10 times more potent for the number of errors and 4 times more potent for the total time taken to complete the task. The relevance of M1 and M2 subtype central acetylcholine receptors in cognitive processes is discussed.
Animals↗