European journal of pharmacology
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The effects of the non-competitive antagonists of the glutamate complex receptor, dizocilpine (MK 801) and ketamine and of the competitive antagonist CGP 39551 were examined on the induction of tolerance to morphine, the development of physical dependence and the expression of the abstinence syndrome to the opiate in mice. Morphine was administered in a single dose (300 mg/kg) of a slow release preparation. ⋯ The drugs also reduced the intensity of the abstinence behaviour when given in a single dose, 30 min before (s.c.) naloxone (4 mg/kg)-precipitated withdrawal syndrome in mice chronically treated with morphine. Thus, the results of this study indicate that competitive and non-competitive NMDA receptor antagonists prevent morphine tolerance and decrease the development of physical dependence on the opiate in mice.
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The nature of the neuroprotection by the competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX), and the non-competitive AMPA receptor antagonist, 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-3,4-dihydro-7,8-methy lenedioxy-5H-2,3-benzodiazepine (GYKI 53655), was investigated in mature telencephalic neurone cultures of the rat. NBQX protected cultured neurones against AMPA-induced delayed toxicity in a competitive manner: the AMPA concentration-response curve was shifted to the right in parallel and concentration dependently. In contrast, GYKI 53655 decreased the maximal neurotoxic effect of AMPA considerably but without affecting the EC50, for AMPA toxicity, which indicated the non-competitive mode of its action. Thus we found a clear relationship between the nature of in vitro neuroprotection and the mode of AMPA channel block.
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The interference of the 5-lipoxygenase inhibitor, BW B70C ((E)-N-(3-[3-(4-fluorophenoxy)phenyl]-1(R,S)-methyl prop-2-enyl)-N-hydroxyurea), with Escherichia coli lipopolysaccharide (endotoxin)-induced lung leucocyte sequestration and microvascular albumin exchanges was evaluated in the anaesthetised guinea-pig using radioactive tracers, in parallel to the effects on cell counts in the broncho-alveolar lavage fluid, blood tumour necrosis factor (TNF-alpha) content, secretion of phospholipase A2 and synthesis of leukotriene C4 by alveolar macrophages. Intravenous injections of 0.1 or 1 mg/kg endotoxin induced lung leucocyte sequestration but only the higher dose induced an increase in albumin microvascular exchanges and the infiltration of leucocytes towards the airway lumen. ⋯ The 5-lipoxygenase inhibitor, BW B70C, injected i.p. (30 mg/kg) prevented leukotriene C4 synthesis by alveolar macrophages and reduced leucocyte migration to the airways lumen as well as albumin microvascular leakage but did not affect the endotoxin-induced increase in the blood level of TNF-alpha and of secreted phospholipase A2. However, BW B70C failed to modify vascular leucocyte margination induced by 1 mg/kg endotoxin, suggesting that, apart from a role of 5-lipoxygenase, alternative pathways operate in response to endotoxin in guinea-pig.
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The effects of selective mu-, delta- and kappa-opioid receptor agonists on the discriminative stimulus properties of cocaine were examined in rats trained to discriminate between cocaine (10 mg/kg) and saline. Cocaine produced a dose-related increase in cocaine-appropriate responses in all of the rats. In generalization tests, neither morphine (mu-opioid receptor agonist) nor N-methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-11-4-benzofu ranacetamide (U50,488H: kappa-opioid receptor agonist) generalized to the discriminative stimulus properties of cocaine. ⋯ Furthermore, the potentiating effect of 3.0 mg/kg morphine on the discriminative stimulus properties of cocaine was attenuated by 2.0 mg/kg U50,488H. In contrast, the potentiating effect of 10 mg/kg TAN-67 on the discriminative stimulus properties of cocaine was not reversed by either 2.0 or 4.0 mg/kg U50,488H. These results suggest that mu-, delta- and kappa-opioid receptor agonists modulate the discriminative stimulus properties of cocaine through different mechanisms, perhaps through different effects on the dopaminergic system.
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NMDA receptors play a critical role in neurotransmission and are also involved in the occurrence of excitotoxic nerve cell death. Synthetic halogenated analogs of the endogenous broad spectrum excitatory amino acid receptor blocker kynurenic acid are among the most potent and selective antagonists of the glycine co-agonist site of the NMDA receptor complex. Pharmacological blockade of this site provides neuroprotection in animal models of cerebral ischemia, epilepsy and neurodegenerative disorders, and does not appear to be associated with some of the undesirable side effects linked to classic competitive and non-competitive NMDA receptor antagonists. ⋯ Intracerebral infusion of 4-Cl-KYN dose-dependently reduced quinolinate neurotoxicity in the rat hippocampus after enzymatic conversion to 7-Cl-KYNA by kynurenine aminotransferase. In accordance with previous studies demonstrating that kynurenine aminotransferase is preferentially localized in astrocytes, both the enzymatic formation of 7-Cl-KYNA and the neuroprotective potency of 4-Cl-KYN were substantially reduced following an intrahippocampal injection of the gliotoxin fluorocitrate. In situ produced 7-Cl-KYNA offers a novel neuroprotective strategy for targeting the glycine/NMDA site while avoiding excessive receptor blockade and reducing the clinical risks associated with conventional NMDA receptor antagonism.