Inhibition of neuronal Ca 2+ influx by gabapentin and pregabalin in the human neocortex

Inhibition of neuronal Ca 2+ influx by gabapentin and pregabalin in the human neocortex 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neuropharmacology Elsevier

Inhibition of neuronal Ca 2+ influx by gabapentin and pregabalin in the human neocortex

Loading next page...
 
/lp/elsevier/inhibition-of-neuronal-ca-2-influx-by-gabapentin-and-pregabalin-in-the-o0nrGw0FjC
Publisher
Elsevier
Copyright
Copyright © 2002 Elsevier Science Ltd
ISSN
0028-3908
eISSN
1873-7064
DOI
10.1016/S0028-3908(01)00172-1
Publisher site
See Article on Publisher Site

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 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.

Journal

NeuropharmacologyElsevier

Published: Feb 1, 2002

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create folders to
organize your research

Export folders, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off