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Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.
- Source :
-
Neuropharmacology [Neuropharmacology] 2002 Feb; Vol. 42 (2), pp. 229-36. - Publication Year :
- 2002
-
Abstract
- Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.
- Subjects :
- Adolescent
Adult
Anticonvulsants
Calcium Channel Blockers pharmacology
Child
Child, Preschool
Female
Gabapentin
Humans
Immunoblotting
Male
Middle Aged
Neocortex cytology
Neocortex drug effects
Neurons drug effects
Norepinephrine metabolism
Potassium metabolism
Pregabalin
Quinoxalines pharmacology
Receptors, AMPA antagonists & inhibitors
Synaptosomes drug effects
Synaptosomes metabolism
omega-Agatoxin IVA pharmacology
Acetates pharmacology
Amines
Calcium metabolism
Cyclohexanecarboxylic Acids
Excitatory Amino Acid Antagonists pharmacology
Neocortex metabolism
Neurons metabolism
gamma-Aminobutyric Acid analogs & derivatives
gamma-Aminobutyric Acid pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0028-3908
- Volume :
- 42
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 11804619
- Full Text :
- https://doi.org/10.1016/s0028-3908(01)00172-1