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 μM 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 ω -agatoxin IVA. The α 2 δ -1, α 2 δ -2, and α 2 δ -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 α 2 δ 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.
Neuropharmacology – Elsevier
Published: Feb 1, 2002
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