Current Opinion in Investigational Drugs

36 Current Opinion in Investigational Drugs 2006 Vol 7 No 1
Several studies have shown that magnesium chloride and the
synthetic polyamine spermine inhibit the binding of gabapentin
to high-affinity binding sites, presumably α2δ subunits, in rats
[39••], mice [59] and pigs [42]. Intrathecal infusion of
magnesium chloride effectively attenuates the anti-allodynic
effect of gabapentin in a rat model [60••]. Nevertheless, the role
of the α2δ subunit in the antineuropathic action of gabapentin is
far from clear. Spermine had no effect on the efficacy of
gabapentin in the same study [60••]. Furthermore, both
magnesium chloride and spermine can promote gabapentin
binding to purified α2δ subunit protein and appear to have a
temperature-dependent effect on the drug in mice, stimulating
binding at 30°C, and inhibiting binding at 4°C [59]. Finally, both
magnesium chloride and spermine are allosteric modulators of
NMDA receptors and could interact with gabapentin through a
different site altogether [61].
K + channel activation
There have been some reports that gabapentin activates
inwardly rectifying K + channels, resulting in membrane
hyperpolarization and decreased excitability [40•,62]. Ng et
al found that gabapentin activates post-synaptic K + currents
in rat brain slices and Xenopus oocytes [40•]. However, this
activation was dependent on expression of a specific cloned
GABAB receptor subtype (gb1a-gb2). Furthermore, GABA
had a similar effect on Xenopus oocytes expressing GABAB
receptors, suggesting that activation of K + currents is a
receptor-mediated effect.
Selective agonism at GABAB receptors (gb1a-gb2)
GABA receptors are of two types; the multi-subunit chloride
channel receptor GABAA subtype, at which gabapentin does
not bind in significant quantities [39••], and the G-proteincoupled
GABAB receptor [63]. Although several studies have
not found that gabapentin binds to any subtype of GABAB
receptors to a significant degree [39••,64••,65], one group has
provided evidence that expression of gb1a-gb2 GABAB
receptors is prerequisite for gabapentin to alter membrane ion
permeability [40•,66]. This is of particular interest because
agonism at GABAB receptors may account for both the
gabapentin-mediated inhibition of voltage-gated Ca 2+ channels
and activation of inwardly rectifying K + channels [67••,68].
A recent pharmacological study provides further evidence
that an important interaction occurs between gabapentin
and the subtype of GABAB receptors constitutively
expressed on pre-synaptic regions of excitatory interneurons
to inhibit excitatory neurotransmitter release [69••].
Importantly, GABAergic neurons were spared, and the
effect of gabapentin on excitatory neurotransmitter release
was sensitive to specific GABAB receptor antagonists. It is
possible that GABAB receptor blockade prevented
gabapentin action by indirect physiological antagonism [70],
as residual GABA is likely to have been present in the rat
brain slices used for this experiment. However, this
postulation does not explain the direct effect of gabapentin
on a GABAB subtype expressed on Xenopus oocytes [40•].
Increased GABA synthesis or release
GABA is an important inhibitory neurotransmitter with
numerous pharmacological interactions [71]. Blockade of
GABA causes hypersensitivity and allodynia consistent with
neuropathic pain [72], and partial nerve injury reduces
dorsal horn synaptic inhibition owing to apoptosis of
GABAergic interneurons [4]. As discussed previously,
gabapentin does not have a direct action at GABAA receptors
[38], GABA-receptor-blocking drugs do not alter the
antineuropathic efficacy of gabapentin [73], and gabapentin
has no effect on GABA reuptake [74]. However, synthesis
and release of GABA in the brain are increased by
gabapentin [75,76], and magnetic resonance imaging
spectroscopy of epileptic patients taking gabapentin
demonstrated a global increase in brain GABA [77]. This
observation may be because of inhibition of GABAtransaminase
[78], activation of glutamic acid decarboxylase
[79] that is sufficient to increase GABA synthesis by 50 to
100% [80], or promotion of non-vesicular GABA release [81].
In an interesting contrast with the finding of Parker et al that
gabapentin acts on pre-synaptic GABAB receptors to inhibit
excitatory neurotransmitter release while sparing
GABAergic neurons [69••], gabapentin increased the
extrasynaptic NMDA-mediated current in GABAergic, but
not non-GABAergic, neurons in a rat model of inflammatory
pain [82,83]. This action may increase activity in inhibitory
spinal cord interneurons, thus releasing GABA under
conditions associated with neuropathic pain. However,
neither NMDA receptor modulation [60••] nor GABA
receptor blockade [73] significantly alters the efficacy of
gabapentin in rat models of pain.
Increase in peripheral whole-blood serotonin
Mood has a profound effect on perception of pain [84], so it
is a realistic possibility that some of the analgesic effects of
gabapentin in humans may be mediated by global
serotonergic activation [85]. Indeed, gabapentin has been
used to treat a variety of mood and anxiety disorders,
although randomized clinical trials have so far been
disappointing [86]. Direct evidence from rats has
contradicted this postulated mechanism; neither pretreatment
of rats with a central nervous system serotonindepleting
compound [73] nor blockade of serotonin
receptors [87] had any effect on the antihyperalgesic efficacy
of gabapentin. We conclude that serotonin is unlikely to be
central to the mechanism of action of gabapentin.
Conclusions
Despite its original conception as a drug designed to mimic
a specific neurotransmitter, gabapentin has become widely
established in clinical practice without a satisfactory
explanation of how it works. As summarized above, debate
regarding its mechanisms of action now centers on the
apparent discrepancy between the high-affinity binding site
on α2δ subunits of voltage-gated Ca 2+ channels [34••], and
persuasive evidence of a direct action at GABAB receptors
[40•].
It has been difficult to distinguish between direct effects of
the drug at Ca 2+ channels and receptor-mediated inhibition
of Ca 2+ current because of an apparently ubiquitous
physiological interdependence. Both actions occur at
therapeutically relevant concentrations, and both may