Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses <i>in vitro</i>

Cunningham, Mark O.; Woodhall, Gavin L.; Thompson, Sarah; Dooley, David; Jones, Roland S.G.

doi:10.1111/j.1460-9568.2004.03625.x

Cited by 130 publications

(118 citation statements)

References 61 publications

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“…The doses (10 -75 M) of gabapentin used in the present study are similar to those tested in other cellular studies such as in rat entorhinal slices (10 -100 M) (Cunningham et al, 2004;Brown and Randall, 2005) and rat trigeminal nucleus (30 M) (Maneuf et al, 2001). In contrast, low concentrations of gabapentin (Ͻ5 M) are effective in DRG (Yang et al, 2005) and high doses are required in cultured neurons (1000 M) (Cheng et al, 2006).…”

Section: Discussionsupporting

confidence: 71%

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Roberto¹,

Gilpin²,

O’Dell³

et al. 2008

J. Neurosci.

118

128

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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 anxiogeniclike effects of ethanol abstinence using an acute dependence model. Gabapentin infused directly into the CeA also blocked dependenceinduced 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.

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Section: Discussionsupporting

confidence: 71%

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Roberto¹,

Gilpin²,

O’Dell³

et al. 2008

J. Neurosci.

118

128

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“…31 It has been suggested that pregabalin may reduce the release of glutamate. 32 Therefore, blockade of the peripheral glutamate receptors by pregabalin in our current neuropathic pain model experiment may be another mechanism of action for reducing the allodynia.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of neuropathy-induced allodynia following intraplantar injection of pregabalin

Park

Joo

Chang

et al. 2010

Can J Anesth/J Can Anesth

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Purpose Pregabalin exhibits potent anticonvulsant, analgesic, and anxiolytic activity in animal models. However, few studies have evaluated pregabalin's potential peripheral effects on neuropathic pain. The aim of this study was to evaluate the peripheral analgesic effects of pregabalin in a rat model of neuropathic pain. Methods Male Sprague-Dawley rats were prepared by ligating the left L5 and L6 spinal nerves to produce neuropathic pain. Sixty rats with neuropathic pain were randomly assigned to six groups. Normal saline (control) and pregabalin (10,20,30, and 50 mgÁkg -1 ) were administered to the plantar surface of the affected left hind paw. Pregabalin (50 mgÁkg -1 ) was administered into the unaffected contralateral paw in order to determine its systemic effect. Responses to mechanical, cold, and heat stimulation were recorded at 15,30, 60, 90, 120, 150, and 180 min after drug administration. Rotarod performance was measured to detect drug-induced side effects, including sedation and reduced motor coordination. Results Saline injected into the affected paw and a pregabalin dose of 50 mgÁkg -1 injected into the contralateral paw showed no differences for mechanical, cold, and heat allodynia. Administration of pregabalin to the affected left hind paw in the dose range of 10-50 mgÁkg -1 resulted in a dose-dependent increase in thresholds to mechanical, cold, and heat stimulation. Conclusion Peripherally administered pregabalin attenuates mechanical, cold, and heat allodynia in a rat model of neuropathic pain. RésuméObjectif La pre´gabaline de´montre une puissante activiteá nticonvulsivante, analge´sique et anxiolytique dans les mode`les animaux. Ne´anmoins, il n'existe que peu d'e´tudes ayant e´value´les effets pe´riphe´riques potentiels de la pre´gabaline sur la douleur neuropathique. L'objectif de cette e´tude e´tait d'examiner les effets analge´siques pe´riphe´riques de la pre´gabaline dans un mode`le de douleur neuropathique chez le rat. Méthode Des rats Sprague-Dawley maˆles ont e´teṕ re´pare´s en ligaturant les nerfs rachidiens L5 et L6 afin de cre´er une douleur neuropathique. Soixante rats souffrant de douleur neuropathique ont e´te´ale´atoirement re´partis en six groupes. Du se´rum physiologique (te´moin) et de la pre´gabaline (10, 20, 30, et 50 mgÁkg -1 ) ont e´te´administre´s a`la surface plantaire de la patte arrie`re gauche affecte´e. De la pre´gabaline (50 mgÁkg -1 ) a e´te´administre´e à la patte controlate´rale non affecte´e afin de de´terminer son effet syste´mique. Les re´actions aux stimulations me´caniques, au froid et a`la chaleur ont e´te´enregistre´es a1 5, 30, 60, 90, 120, 150 et 180 min apre`s l'administration du me´dicament. La performance au test de la tige tournante a e´te´mesure´e afin de de´pister les effets secondaires provoque´s par le me´dicament, notamment la se´dation et une re´duction de la coordination motrice.This article is accompanied by an editorial. Please see Can J Anesth 2010; 57(7).

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“…100 -102 Other studies have shown inhibition of the release of glutamate and other neurotransmitters. [103][104][105] The variability in the effects on Ca 2ϩ current may relate to differences in expression of the ␣2-␦ subunit in different cell types or in response to different conditions. For example, in chronic neuropathic pain states, ␣2-␦ subunits may be upregulated, conferring gabapentin and pregabalin sensitivity.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro

Cited by 130 publications

References 61 publications

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Attenuation of neuropathy-induced allodynia following intraplantar injection of pregabalin

Molecular Targets for Antiepileptic Drug Development

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