The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Mar 1999
Effect of riluzole on the neurological and neuropathological changes in an animal model of cardiac arrest-induced movement disorder.
Posthypoxic myoclonus and seizures precipitate as secondary neurological consequences in ischemic/hypoxic insults of the central nervous system. Neuronal hyperexcitation may be due to excessive activation of glutamatergic neurotransmission, an effect that has been shown to follow ischemic/hypoxic events. Therefore, riluzole, an anticonvulsant that inhibits the release of glutamate by stabilizing the inactivated state of activated voltage-sensitive sodium channels, was tested for its antimyoclonic and neuroprotective properties in the cardiac arrest-induced animal model of posthypoxic myoclonus. ⋯ The neuroprotective effect was more pronounced in hippocampal pyramidal neurons and cerebellar Purkinje cells. These effects were seen at therapeutically relevant doses of riluzole, and the animals tolerated the treatment well. These findings indicate that the pathogenesis of posthypoxic myoclonus and seizure may involve excessive activation of glutamate neurotransmission, and that riluzole may serve as an effective pharmacological agent with neuroprotective potential for the treatment of neurological conditions associated with cardiac arrest in humans.
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J. Pharmacol. Exp. Ther. · Mar 1999
Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats.
Repetitive ectopic discharges from injured afferent nerves play an important role in initiation and maintenance of neuropathic pain. Gabapentin is effective for treatment of neuropathic pain but the sites and mechanisms of its antinociceptive actions remain uncertain. In the present study, we tested a hypothesis that therapeutic doses of gabapentin suppress ectopic afferent discharge activity generated from injured peripheral nerves. ⋯ However, the conduction velocity and responses of 12 normal afferent fibers to mechanical stimulation were not affected by gabapentin. Therefore, this study provides electrophysiological evidence that gabapentin is capable of suppressing the ectopic discharge activity from injured peripheral nerves. This action may contribute, at least in part, to the antiallodynic effect of gabapentin on neuropathic pain.
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J. Pharmacol. Exp. Ther. · Feb 1999
Randomized Controlled Trial Clinical TrialContribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan.
Dextromethorphan (DEM)-mediated N-methyl-D-aspartate receptor blockade may result from an action of unchanged DEM or its active metabolite, dextrorphan (DOR). In humans, DEM is metabolized into DOR by the polymorphic enzyme CYP2D6. We therefore investigated the impact of quinidine (Qd), a selective inhibitor of CYP2D6, on DEM disposition and the contribution of CYP2D6 phenotype on DEM antinociceptive and neuromodulatory effects. ⋯ DEM modulates secondary hyperalgesia compared with DOR. The CYP2D6 phenotype affects the disposition of DEM and the production of the active metabolite DOR. The impact of the CYP2D6 phenotype is of major importance for the spinal antinociceptive and neuromodulatory effects of DEM.
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J. Pharmacol. Exp. Ther. · Feb 1999
Comparative StudyThe effects of morphine, nicotine and epibatidine on lymphocyte activity and hypothalamic-pituitary-adrenal axis responses.
Acute administration of morphine alters various neuroendocrine and immune parameters via opioid receptors located within the central nervous system. Similar effects have been reported after systemic nicotine treatment. To examine the possible relationship between opioid and nicotinic receptor activation on the immune system, we compared the effects of morphine with both nicotine and the highly selective nicotinic agonist, epibatidine. ⋯ Furthermore, in contrast to morphine (), central injection of neither nicotine (30 or 240 nmol) nor epibatidine (5, 50, or 500 ng) altered blood lymphocyte responses. These results suggest that, like morphine, nicotinic agonists decrease blood lymphocyte proliferation responses, apparently independent of elevated corticosterone. However, unlike morphine, nicotinic agonists appear to act predominantly at peripheral receptors, suggesting that nicotinic receptors are downstream of opioid receptors in a centrally mediated opioid-induced immunomodulatory pathway.
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J. Pharmacol. Exp. Ther. · Feb 1999
Age-related changes in the capacity, rate, and modulation of dopamine uptake within the striatum and nucleus accumbens of Fischer 344 rats: an in vivo electrochemical study.
Age-related changes in the capacity, rate, and modulation of dopamine (DA) uptake within the striatum and the nucleus accumbens core of Fischer 344 rats were investigated using in vivo electrochemical recordings coupled with local drug application techniques. Equimolar amounts of DA were pressure ejected into the striatum and the nucleus accumbens of 6-, 12-, 18-, and 24-month old rats. The DA ejections produced larger DA signal amplitudes in the older rats, suggesting age-related differences in the capacity to clear extracellular DA. ⋯ The maximum rate of DA transport was significantly reduced in both the striatum and the nucleus accumbens of aged rats (18 and 24 months versus 6 and 12 months). The ability of nomifensine, an inhibitor of the DA transporter, to modulate DA signal amplitudes in the striatum and the nucleus accumbens was also decreased with age (24 months versus 6 months). Taken together, these findings demonstrate substantial age-related deficits in DA uptake processes within the striatum and the nucleus accumbens, consistent with the hypothesis that DA uptake may be slowed in aged animals to compensate for reductions in DA release.