Gabapentin inhibits presynaptic Ca2+ influx and synaptic transmission in rat hippocampus and neocortex

Swammerdam Institute for Life Sciences, Neurobiology Section, University of Amsterdam, P.O. Box 94084, NL-1090 GB, Amsterdam, The Netherlands.
European Journal of Pharmacology (Impact Factor: 2.53). 09/2002; 449(3):221-28. DOI: 10.1016/S0014-2999(02)02044-7
Source: PubMed

ABSTRACT Gabapentin is a widely used drug with anticonvulsant, antinociceptive and anxiolytic properties. Although it has been previously shown that Gabapentin binds with high affinity to the alpha(2)delta subunit of voltage-operated Ca(2+) channels (VOCC), little is known about the functional consequences of this interaction. Here, we investigated the effect of Gabapentin on VOCCs and synaptic transmission in rat hippocampus and neocortex using whole-cell patch clamp and confocal imaging techniques. Gabapentin (100-300 microM) did not affect the peak amplitude or voltage-dependency of VOCC currents recorded from either dissociated or in situ neocortical and hippocampal pyramidal cells. In contrast, Gabapentin inhibited K(+)-evoked increases in [Ca(2+)] in a subset of synaptosomes isolated from rat hippocampus and neocortex in a dose-dependent manner, with an apparent half-maximal inhibitory effect at approximately 100 nM. In hippocampal slices, Gabapentin (300 microM) inhibited the amplitude of evoked excitatory- and inhibitory postsynaptic currents recorded from CA1 pyramidal cells by 30-40%. Taken together, the results suggest that Gabapentin selectively inhibits Ca(2+) influx by inhibiting VOCCs in a subset of excitatory and inhibitory presynaptic terminals, thereby attenuating synaptic transmission.

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Available from: Johannes A van Hooft, Sep 28, 2015
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    • "However, it is widely accepted that the mechanism of action of these agents involves a modulation of calcium conductance, but the precise mechanism for this remains to be elucidated. The modulation of calcium currents by gabapentin has been demonstrated in several studies of isolated neurones (Stefani et al., 1998; Sutton et al., 2002; van Hooft et al., 2002), although other studies have struggled to demonstrate such an effect (Schlicker et al., 1985). More recently, it has been proposed that gabapentin may exert an action through binding to the α 2 δ subunit within the cytosol, rather than at the cell surface, and that this interaction can over time reduce the trafficking of α 1 /α 2 δ complexes to functional sites within the cell membrane (Hendrich et al., 2008; Mich and Horne, 2008). "
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    ABSTRACT: Irritable bowel syndrome (IBS) is a complex disorder that is characterized by abdominal pain and altered bowel habit, and often associates with other gastrointestinal symptoms such as feelings of incomplete bowel movement and abdominal bloating, and extra-intestinal symptoms such as headache, dyspareunia, heartburn, muscle pain, and back pain. It also frequently coexists with conditions that may also involve central sensitization processes, such as fibromyalgia, irritable bladder disorder, and chronic cough. This review examines the evidence to date on gabapentin and pregabalin which may support further and continued research and development of the α(2)δ ligands in disorders characterized by visceral hypersensitivity, such as IBS. The distribution of the α(2)δ subunit of the voltage-gated calcium channel, possible mechanisms of action, pre-clinical data which supports an effect on motor-sensory mechanisms and clinical evidence that points to potential benefits in patients with IBS will be discussed.
    Frontiers in Pharmacology 06/2011; 2:28. DOI:10.3389/fphar.2011.00028 · 3.80 Impact Factor
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    • "The GABA analogue gabapentin was originally developed to treat epilepsy [4], but it is now widely used to alleviate neuropathic pain [3]. Accumulating evidence from diverse animal models of neuropathic pain suggests that the anti-allodynic effects of gabapentin are associated with the modulation of neurotransmitter release or neuronal excitability resulting from alterations in Ca2+ currents [5,6]. The α2δ subunit, but not the pore-forming α1 or β subunits, of voltage-dependent Ca2+ channels (VDCC) in the spinal cord and dorsal root ganglion (DRG) is upregulated in gabapentin-sensitive pain models such as mechanical- and diabetic-neuropathic types, but not in the gabapentin-insensitive chemical model of neuropathic pain [7-9]. "
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    ABSTRACT: Neuropathic pain is characterized by hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to NSAIDs or even opioids. Gabapentin, a GABA analogue, was originally developed to treat epilepsy. Accumulating clinical evidence supports the effectiveness of this drug for diverse neuropathic pain. In this study, we showed that the anti-allodynic effect of gabapentin was changed by the circadian oscillation in the expression of its target molecule, the calcium channel α2δ-1 subunit. Mice were underwent partial sciatic nerve ligation (PSL) to create a model of neuropathic pain. The paw withdrawal threshold (PWT) in PSL mice significantly decreased and fluctuated with a period length about 24 h. The PWT in PSL mice was dose-dependently increased by intraperitoneal injection of gabapentin, but the anti-allodynic effects varied according to its dosing time. The protein levels of α2δ-1 subunit were up-regulated in the DRG of PSL mice, but the protein levels oscillated in a circadian time-dependent manner. The time-dependent oscillation of α2δ-1 subunit protein correlated with fluctuations in the maximal binding capacity of gabapentin. The anti-allodynic effect of gabapentin was attenuated at the times of the day when α2δ-1 subunit protein was abundant. These findings suggest that the dosing time-dependent difference in the anti-allodynic effects of gabapentin is attributable to the circadian oscillation of α2δ-1 subunit expression in the DRG and indicate that the optimizing its dosing schedule helps to achieve rational pharmacotherapy for neuropathic pain.
    Molecular Pain 11/2010; 6(1):83. DOI:10.1186/1744-8069-6-83 · 3.65 Impact Factor
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    • "A series of studies in other laboratories have shown that gabapentin effects involve GABA B receptors, at least in part (Xiong and Stringer, 1997; Stringer and Lorenzo, 1999; Parker et al., 2004). Gabapentin acts as an agonist at GABA B receptors coupled to VOCC in mouse cultured neurons (Bertrand et al., 2001; van Hooft et al., 2002). Neverthless, despite this compelling evidence, conventional binding studies failed to demonstrate a direct interaction between gabapentin and GABA B receptors (Lanneau et al., 2001; Jensen et al., 2002). "
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    ABSTRACT: Gabapentin is a structural analog of GABA that has anticonvulsant properties. Despite the therapeutic efficacy of gabapentin, its molecular and cellular mechanisms of action are unclear. The GABAergic system in the central nucleus of the amygdala (CeA) plays an important role in regulating voluntary ethanol intake. Here, we investigated the effect of gabapentin on GABAergic transmission in CeA slices, on ethanol intake, and on an anxiety measure using animal models of ethanol dependence. Gabapentin increased the amplitudes of evoked GABA receptor-mediated IPSCs (GABA-IPSCs) in CeA neurons from nondependent rats, but decreased their amplitudes in CeA of ethanol-dependent rats. Gabapentin effects were blocked in the presence of a specific GABA(B) receptor antagonist. The sensitivity of the GABA-IPSCs to a GABA(B) receptor antagonist and an agonist was decreased after chronic ethanol, suggesting that ethanol-induced neuroadaptations of GABA(B) receptors associated with ethanol dependence may account for the differential effects of gabapentin after chronic ethanol. Systemic gabapentin reduced ethanol intake in dependent, but not in nondependent, rats and reversed the anxiogenic-like effects of ethanol abstinence using an acute dependence model. Gabapentin infused directly into the CeA also blocked dependence-induced elevation in operant ethanol responding. Collectively, these findings show that gabapentin reverses behavioral measures of ethanol dependence and, in turn, dependence reverses the effects of gabapentin on CeA neurons, and suggest that gabapentin represents a potential medication for treatment of alcoholism.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2008; 28(22):5762-71. DOI:10.1523/JNEUROSCI.0575-08.2008 · 6.34 Impact Factor
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