European journal of pharmacology
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Comparative Study
Characterization of A-425619 at native TRPV1 receptors: a comparison between dorsal root ganglia and trigeminal ganglia.
1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea (A-425619), a novel, potent, and selective transient receptor potential type V1 (TRPV1) antagonist, attenuates pain associated with inflammation and tissue injury in rats. The purpose of this study was to extend the in vitro characterization of A-425619 to native TRPV1 receptors and to compare the pharmacological properties of TRPV1 receptors in the dorsal root ganglion with trigeminal ganglion neurons. A robust increase in intracellular Ca(2+) was elicited by a variety of TRPV1 agonists with similar rank order of potency between both cultures: resiniferatoxin>tinyatoxin>capsaicin>N-arachidonoyl-dopamine (NADA). ⋯ Electrophysiology studies showed that 100 nM A-425619 completely inhibited TRPV1-mediated acid activated currents in dorsal root ganglia and trigeminal ganglia neurons. In addition, A-425619 blocked capsaicin- and NADA-evoked calcitonin gene-related peptide (CGRP) release in both cultures more effectively than capsazepine. These data show that A-425619 is a potent TRPV1 antagonist at the native TRPV1 receptors, and suggest that the pharmacological profile for TRPV1 receptors on dorsal root ganglia and trigeminal ganglia is very similar.
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Acetylsalicylic acid (aspirin) is often given together with other nonsteroidal anti-inflammatory drugs and acetaminophen. The latter have been accused in epidemiologic studies to cause an increased cardiovascular risk. We have, therefore, analysed the influence of various such drug combinations on platelet aggregation in vitro. ⋯ We conclude that acetaminophen by itself does not affect platelet aggregation, but potentiates the antiaggregatory effect of aspirin or diclofenac. Aspirin given before acetaminophen or diclofenac had a more potent antiaggregatory effect than vice versa. These observations may have clinical implications.
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The aim of this study was to characterize the pharmacodynamic, pharmacokinetic and adverse-effect profiles of vigabatrin and gabapentin. Isobolographic analysis was used in two mouse experimental models of epilepsy: the maximal electroshock seizure threshold test and pentylenetetrazole-induced seizures. In the maximal electroshock seizure threshold test, electroconvulsions were produced by a current with various intensities whilst in the pentylenetetrazole test a CD(97) dose (100 mg/kg) was used. ⋯ In combination neither motor coordination nor skeletal muscular strength was affected. Total vigabatrin and gabapentin brain concentrations revealed that neither drug affected the pharmacokinetics of the other. Vigabatrin and gabapentin have a favorable pharmacodynamic interaction in animal seizure models in the absence of acute adverse effects or concurrent pharmacokinetic changes.
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We previously reported the synthesis of three new opioid agonists as well as their in vitro and in vivo activity [Girón, R., Abalo, R., Goicoechea, C., Martín, M. I., Callado, L. F., Cano, C., Goya, P., Jagerovic, N. 2002. ⋯ An interesting feature of the new compound is that it induces tolerance in vitro but not in vivo. Moreover, though in vitro withdrawal was not different from fentanyl or morphine, in vivo withdrawal symptoms were significantly less frequent in mice treated with IQMF-4 than in those treated with morphine or fentanyl. Although more assays are required, these results show that IQMF-4 appears to be a potent analgesic compound with an interesting peripheral component, and reduced ability to induce dependence.
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Nitric oxide (NO) or glutamate stimulation of dorsal facial area (DFA) increases blood flow in the common carotid artery (CCA), which supplies intra-and extra-cranial tissues. Nitrergic fibers and neurons as well as preganglionic cholinergic neurons are present in the DFA. We hypothesized the presence of nitrergic-glutamatergic fibers and preganglionic nitrergic-cholinergic neurons in the DFA that are involved in the regulation of CCA blood flow. ⋯ The induced increase in CCA blood flow, however, was not affected by endothelial NO synthase inhibitor. The findings indicate that NO-signal transduction within the DFA might cause glutamate release from presynaptic nitrergic-glutamatergic fibres and that the released glutamate activates NMDA/AMPA receptors on preganglionic nitrergic-cholinergic neurons in the nucleus to activate neuronal NO synthase and guanylyl cyclase in the neurons, leading to an increase in CCA blood flow. These findings may be important for developing therapeutic strategies for the diseases associated with CCA blood flow.