British journal of pharmacology
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In a hamster model (genetic symbol dt(sz)) of primary paroxysmal non-kinesiogenic dystonic choreoathetosis, recent studies have shown beneficial effects of glutamate and dopamine receptor antagonists. Nitric oxide (NO), synthesized from L-arginine by NO synthase in response to glutamate receptor activation, elicits cyclic GMP and modulates glutamate-mediated processes and striatal dopamine release. Therefore, the effects of NO synthase inhibitors and of L-arginine on severity of dystonia were investigated in dt(sz) hamsters in which dystonic attacks, characterized by twisting movements and postures, can be induced by stress. ⋯ L-NAME significantly decreased the cerebellar cyclic GMP levels in both dt(sz) and control hamsters. Although an overproduction of NO is probably not critically involved in the pathogenesis of paroxysmal dystonia, it may contribute to the manifestation of dystonic attacks, as indicated by the antidystonic effects of NO synthase inhibitors. Peripheral side effects may limit the clinical use of NO synthase inhibitors, but more selective inhibitors of the neuronal NO synthase should be considered as interesting candidates for the treatment of paroxysmal dystonia.
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This study examined the effects of the peptide CGRP receptor antagonist CGRP(8-37) and the newly-developed non-peptide CGRP receptor antagonist BIBN4096BS for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. Repeated administration of intrathecal morphine (15 microg), once daily, produced a progressive decline of antinociceptive effect and an increase in the ED(50) value in the tailflick and paw pressure tests. Co-administration of CGRP(8-37) (4 microg) or BIBN4096BS (0.05, 0.1 microg) with morphine (15 microg) prevented the decline of antinociceptive effect and increase in ED(50) value in the tailflick test. ⋯ In animals already tolerant to morphine, the increase in CGRP but not substance P-like immunostaining was partially reversed by CGRP(8-37) (4 microg). These data suggest that activation of spinal CGRP receptors contributes to both the development and expression of spinal opioid tolerance. CGRP receptor antagonists may represent a useful therapeutic approach for preventing as well as reversing opioid tolerance.
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1. Current analgesic therapy is dominated by NSAIDs and opiates, however these agents have limited efficacy in the treatment of neuropathic pain. The novel anticonvulsant agent gabapentin (Neurontin) has been shown to be an effective treatment for neuropathic pain in the clinic. ⋯ This isomer also dose-dependently blocked the maintenance of dynamic allodynia in both models with respective MEDs of 30 and 100 mg kg(-1). In contrast, (1R,3R) 3-methyl gabapentin (100 mg kg(-1), p.o.) failed to block either static or dynamic allodynia in the streptozocin model. 4. It is concluded that these data further support the hypothesis that the alpha(2)delta subunit of VDCCs plays an important role in the maintenance of mechanical hypersensitivity in models of neuropathic pain.
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The aim of this study was to elucidate the in vitro inhibitory potency of FK506 on production of the inflammatory cytokines, tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta, with a view to assessing this immunosuppressive agent as a potential anti-rheumatic drug. We employed an in vitro model which produces TNF-alpha and IL-1beta through T cell activation. Human peripheral blood mononuclear cells (PBMC) were cultured with immobilized anti-CD3/CD28 monoclonal antibody in this model. ⋯ FK506, CsA and DEX led to the suppression of adhesion molecule expression probably by inhibiting cytokine production from PBMC. The inhibitory potency of agents on TNF-alpha and IL-1beta production was compared with cytotoxicity and FK506 was not cytotoxic at concentrations several orders of magnitude greater than those required for cytokine inhibition. These results strongly suggest that FK506 may be most effective to specifically prevent T cell activation mediated inflammatory cytokine production in a clinical setting.
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For general anaesthesia, patients usually receive a combination of drugs, all of which are classified as gamma-amino-butyric acid (GABA) agonists, with two notable exceptions - ketamine and nitrous oxide (laughing gas, N(2)O) - which are antagonists of N-methyl-D-aspartate (NMDA) glutamate receptors. At clinically relevant doses both ketamine and N(2)O, like other NMDA antagonists, have the potential to induce psychotomimetic reactions in humans and to cause pathomorphological changes in cerebrocortical neurons in rat brain. Because drug combinations used in clinical anaesthesia sometimes include both ketamine and N(2)O, we undertook experiments to evaluate whether augmented neurotoxicity results from their combined use. ⋯ The apparent synergistic interaction was particularly striking when low doses of the agents were combined, the degree of toxic synergism at higher doses being masked by a ceiling effect. GABA agonists protected against ketamine/N(2)O neurotoxicity. It is recommended that this information be taken into consideration in the selection of drugs to be used in multi-agent protocols for general anaesthesia.