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Titolo:
The in vivo relevance of the varied channel-blocking properties of uncompetitive NMDA antagonists: tests on spinal neurones
Autore:
Jones, MW; McClean, M; Parsons, CG; Headley, PM;
Indirizzi:
Sch Med Sci Bristol, Dept Physiol, Bristol BS8 1TD, Avon, England Sch Med Sci Bristol Bristol Avon England BS8 1TD l BS8 1TD, Avon, England Merz & Co, Dept Pharmacol, D-60318 Frankfurt, Germany Merz & Co Frankfurt Germany D-60318 harmacol, D-60318 Frankfurt, Germany
Titolo Testata:
NEUROPHARMACOLOGY
fascicolo: 1, volume: 41, anno: 2001,
pagine: 50 - 61
SICI:
0028-3908(200107)41:1<50:TIVROT>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
D-ASPARTATE RECEPTOR; N-METHYLASPARTATE RECEPTORS; MOUSE CENTRAL NEURONS; DORSAL HORN; IN-VIVO; NOCICEPTIVE REFLEXES; DEPENDENT BLOCK; AMINO-ACIDS; WIND-UP; RAT;
Keywords:
N-methyl-D-aspartate; voltage dependence; nociception; wind-up; inflammation; spinal cord;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
46
Recensione:
Indirizzi per estratti:
Indirizzo: Headley, PM Sch Med Sci Bristol, Dept Physiol, Univ Walk, Bristol BS8 1TD,Avon, England Sch Med Sci Bristol Univ Walk Bristol Avon England BS8 1TD and
Citazione:
M.W. Jones et al., "The in vivo relevance of the varied channel-blocking properties of uncompetitive NMDA antagonists: tests on spinal neurones", NEUROPHARM, 41(1), 2001, pp. 50-61

Abstract

The voltage dependence and channel-blocking kinetics of uncompetitive NMDAreceptor antagonists have been well-described using in vitro techniques, but there is little evidence concerning the functional significance of theseproperties in vivo. We have now compared the effects of NMDA antagonists that display varied profiles of voltage-dependent block in vitro, on responses of spinal neurones in anaesthetised rats. The compounds examined were the uncompetitive channel blockers memantine, ketamine and MK-801 and, for comparison, an antagonist that acts at the strychnine insensitive glycine binding site (MRZ 2/502). Using frequency of spike discharge as an indicator of somatic depolarisation, we have compared the effects of these antagonistson responses evoked by iontophoretic NMDA application and on synaptic responses evoked by pinch or electrical stimulation (the latter eliciting "wind-up"). The effectiveness of the antagonists was directly but variably related to the discharge frequency of the test response. The rank order of dependence on firing rate matched the rank order of voltage dependence reported in vitro, namely: memantine > ketamine > MK-801 greater than or equal to MRZ 2/502. Doses that reduced responses to iontophoretic application of NMDA were less effective at reducing responses to pinch, perhaps due to the major non-NMDA component of the synaptic response. Memantine preferentially reduced "wind-up" relative to responses to pinch, whereas ketamine and MK-801 reduced both types of synaptic responses in parallel. This "filtering" by low affinity, voltage-dependent NMDA antagonists such as memantine. of non-physiological activity whilst leaving normal synaptic events relatively untouched, may contribute to their more favourable clinical profile. (C) 2001 Elsevier Science Ltd. All rights reserved.

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Documento generato il 07/07/20 alle ore 12:31:45