Life sciences
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Comparative Study
Inhibitory effects of TRK-820 on systemic skin scratching induced by morphine in rhesus monkeys.
The inhibitory effects of kappa-opioid receptor agonists on systemic skin scratching induced by the intravenous administration of morphine, a micro-opioid receptor agonist, were investigated in rhesus monkeys. Intravenous pretreatment with kappa-opioid receptor agonists, either TRK-820 at 0.25 and 0.5 microg/kg or U-50488H at 64 and 128 microg/kg, inhibited systemic skin scratching induced by morphine at 1 mg/kg, i.v. in a dose-dependent manner. By the intragastric route, apparent inhibitory effects on morphine-induced systemic skin scratching were evident following pretreatment with TRK-820 at 4 microg/kg but not with U-50488H from 512 to 2048 microg/kg. These results suggest that TRK-820 produces antipruritic effects on i.v. morphine-induced systemic skin scratching and is more readily absorbed intragastrically than is U-50488H, resulting in high bioavailability in the intragastric route.
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Comparative Study
High concentrations of alpha-defensins in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome.
alpha-Defensins, antimicrobial peptides localized in neutrophils, participate in tissue damage through their cytotoxic effects in neutrophil-mediated pulmonary diseases. Neutrophils play an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). We measured alpha-defensins levels in plasma and bronchoalveolar lavage fluid (BALF) of ARDS patients to assess the kinetics of alpha-defensins in ARDS. ⋯ Reverse-phase high performance liquid chromatography showed high plasma levels of pro-defensins, precursors of alpha-defensins from the bone marrow in ARDS, although alpha-defensins in peripheral and BALF neutrophils were mature type. In conclusion, high plasma alpha-defensins in ARDS patients result from the release of pro-defensins from bone marrow, rather than mature alpha-defensins from neutrophils that accumulate in the alveolar space. The alpha-defensins contents of peripheral neutrophils in ARDS are higher and easier to release than control.
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Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) have been previously implicated in the late phase of cardioprotection associated with opioid-induced and ischemic preconditioning (IPC) in conscious rabbits and COX-2 in isolated rat hearts pretreated with an exogenous delta opioid agonist. However, it is not know if both iNOS and COX-2 mediate the late phase of cardioprotection induced by opioids in the intact blood-perfused rat. Therefore, we investigated the role of COX-2 and iNOS in the delayed phase of protection mediated by delta opioid receptor activation. ⋯ However, the delayed protective effects of the opioids were not attenuated by pretreatment with the iNOS inhibitors 24 hours prior to the infarct protocol. These results suggest that both COX-2 and iNOS are mediators of delayed protection induced by non-peptide delta opioid agonists. It appears that the trigger effect is not dependent on the activity of iNOS or COX-2 but the late phase of cardioprotection is dependent on the upregulation of these enzymes.
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The present study set out to investigate the pharmacological profile of the cardiovascular responses induced by the antimigraine agent, isometheptene, in pithed rats. For this purpose, intravenous (i.v.) administration of blocking doses of the antagonists prazosin (alpha1; 100 microg/kg), rauwolscine (alpha2; 300 microg/kg), the combination of prazosin (100 microg/kg) plus rauwolscine (300 microg/kg), propranolol (beta; 1000 microg/kg), ritanserin (5-HT2; 100 microg/kg) or equivalent volumes of saline (1 ml/kg) were used. Isometheptene (0.03, 0.1, 0.3, 1 and 3 mg/kg, i.v.) produced dose-dependent increases in heart rate and diastolic blood pressure which were highly reproducible as they remained unaltered after saline. ⋯ In contrast, the isometheptene-induced vasopressor responses were not significantly modified after the above doses of rauwolscine, ritanserin or propranolol, but were markedly blocked after prazosin or the combination of prazosin plus rauwolscine; the latter blockade did not significantly differ from that produced by prazosin alone. Interestingly, in rats pretreated intraperitoneally (i.p.) with reserpine (5 mg/kg; -24 h), isometheptene-induced tachycardic responses were abolished whereas the corresponding vasopressor responses were markedly attenuated and subsequently blocked by prazosin. It is concluded that isometheptene-induced tachycardic responses seem to involve only an indirect (tyramine-like action) mechanism mediated by beta-adrenoceptors, whilst the corresponding vasopressor responses are mediated by a predominantly indirect (tyramine-like action), as well as a minor direct (alpha1-adrenoceptors), sympathomimetic mechanism.
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The effects of (R)- and (S)-optical isomers of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and of the racemate (R,S)-8-OH-DPAT on serotonin (5-HT) release in the ventral hippocampus of awake rats and on induction of the whole-body hypothermia were studied. Extracellular 5-HT levels were determined by a newly developed high-sensitive HPLC method based on derivatization with benzylamine and fluorescence detection. The basal levels of 5-HT in 20 min microdialysates from rats perfused with Ringer solution or with Ringer solution containing 1 microM citalopram were 6.3 +/- 1.3 fmol/20 microl and 36.1 +/- 4.2 fmol/20 microl (n=20), respectively. ⋯ Injection of (R)-8-OH-DPAT (0.3 mg/kg s.c.) caused further reduction of 5-HT levels, to 49% and 41%, respectively, whereas (S)-8-OH-DPAT (0.3 mg/kg s.c.) caused maximal reduction of 5-HT levels only to 74% of controls in both perfusion groups. Similar pattern and time-courses were observed in rats with hypothermia induced by injection of 8-OH-DPAT enantiomers, where (R,S), (R)-forms were about two-times more potent than the (S)-isomer. It is concluded that the acute systemic dose of (R)-, (S)- and (R,S)-8-OH-DPAT enantiomers exerted enantiomer-specific effects on 5-HT(1A) receptor-mediated function both at the presynaptic and postsynaptic sites as revealed by monitoring hippocampal 5-HT levels and body temperature.