A study comparing the actions of gabapentin and pregabalin on the electrophysiological properties of cultured DRG neurones from neonatal rats

McClelland, David; Evans, Rhian M.; Barkworth, Louise; Martin, Duncan J.; Scott, Roderick H.

doi:10.1186/1471-2210-4-14

Cited by 83 publications

(23 citation statements)

References 49 publications

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“…These data suggest the enhanced calcium entry seen with KCl stimulation was not due to direct effects of gabapentin on I Ca . Pregabalin was previously reported to enhance Ca 2+ entry in a subset of sensory neurons perhaps through modulation of K + channels 47 , but we did not investigate this possibility in the current study.…”

Section: Discussionmentioning

confidence: 81%

Gabapentin Inhibits Catecholamine Release from Adrenal Chromaffin Cells

Todd

McDavid²,

Brindley

et al. 2012

Anesthesiology

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Background Gabapentin is most commonly prescribed for chronic pain, but acute perioperative effects including preemptive analgesia and hemodynamic stabilization have also been reported. Adrenal chromaffin cells are a widely used model to investigate neurosecretion and adrenal catecholamines play important physiological roles and contribute to the acute stress response. However, the effects of gabapentin on adrenal catecholamine release have never been tested. Methods Primary cultures of bovine adrenal chromaffin cells were treated with gabapentin or vehicle for 18–24 h. We quantified catecholamine secretion from dishes of cells using high performance liquid chromatography, and resolved exocytosis of individual secretory vesicles from single cells using carbon fiber amperometry. Voltage-gated calcium channel currents (ICa) were recorded using patch-clamp electrophysiology, and intracellular [Ca2+] using fluorescent imaging. Results Gabapentin produced statistically significant reductions in catecholamine secretion evoked by cholinergic agonists (24 ± 3 % n = 12) or KCl (16 ± 4 % n = 8) (mean ± SEM) but did not inhibit Ca2+ entry or ICa. Amperometry (n = 51 cells) revealed that gabapentin inhibited the number of vesicles released upon stimulation, with no change in quantal size or kinetics of these unitary events. Conclusions We show Ca2+ entry was not inhibited by gabapentin, but was less effective at triggering vesicle fusion. Our work also demonstrates that chromaffin cells are a useful model to further investigate the cellular mechanism(s) by which gabapentin controls neurosecretion. Moreover, it identifies altered adrenal catecholamine release as a potential contributor to some of the beneficial perioperative effects of gabapentin.

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Section: Discussionmentioning

confidence: 81%

Gabapentin Inhibits Catecholamine Release from Adrenal Chromaffin Cells

Todd

McDavid²,

Brindley

et al. 2012

Anesthesiology

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“…While some previous studies report no acute effect of gabapentin on calcium channels (Rock et al, 1993; Kang et al, 2002; Davies et al, 2006); several studies have documented inhibitory effects of gabapentin on VGCCs even with brief applications of the drug (Stefani et al, 1998, 2001; Martin et al, 2002; McClelland et al, 2004). There are several possibilities for the discrepancy in responsiveness of neuronal cells to gabapentin (reviewed by Uchitel et al, 2010).…”

Section: Discussionmentioning

confidence: 93%

Modulation of voltage-gated Ca²⁺ channels in rat retinal ganglion cells by gabapentin

et al. 2013

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The α2δ auxiliary subunits of voltage-gated Ca2+ channels (VGCCs) are important modulators of VGCC function. Gabapentin interacts with α2δ1 and α2δ2 subunits and is reported to reduce Ca2+ channel current amplitude (ICa). This study aimed to determine the effects of gabapentin on VGCCs in retinal ganglion cells (RGCs). Whole cell patch clamp was used to record ICa in isolated RGCs, and calcium imaging was used to measure Ca2+ transients from RGCs in situ. Immunohistochemistry was used to detect the presence of α2δ1-containing VGCCs in isolated RGCs in the absence and presence of gabapentin pretreatment. Acute administration of gabapentin reduced ICa and Ca2+ transients compared to control conditions. In isolated RGCs, pretreatment with gabapentin (4–18 h) reduced ICa, and cell surface α2δ1 staining was reduced compared to nonpretreated cells. Acute administration of gabapentin to isolated RGCs that had been pretreated further reduced ICa. These results show that gabapentin has both short-term and long-term mechanisms to reduce ICa in isolated RGCs. Some Ca2+ channel blockers have been shown to protect RGCs in retinal trauma suggesting that modulation of VGCCs by gabapentin may prevent the deleterious effects of elevated Ca2+ levels in RGCs in trauma and disease.

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“…This is further supported by the observation that some α 2 δ ligands, pregabalin and L-isoleucine, enhance glutamate-induced intracellular Ca 2+ response, while another (ABHCA) did not, despite similar α 2 δ binding affinity of ABHCA as gabapentin (Lynch et al, 2006). In some neurons, pertussis toxin-sensitive G-protein pathways are critical for action of gabapentinoids on ion channels (Bertrand et al, 2003; McClelland et al, 2004). In astrocytes, pertussis toxin itself increases glutamate uptake but reduces noradrenaline-induced facilitation of glutamate uptake in astrocytes (Fahrig, 1993).…”

Section: Discussionmentioning

confidence: 99%

Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes

Yoshizumi

Eisenach

Hayashida

2012

European Journal of Pharmacology

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We have recently demonstrated that the glutamate transporter activator riluzole paradoxically enhanced glutamate-induced glutamate release from cultured astrocytes. We further showed that both riluzole and the α2δ subunit ligand gabapentin activated descending inhibition in rats by increasing glutamate receptor signaling in the locus coeruleus and hypothesized that these drugs share common mechanisms to enhance glutamate release from astrocytes. In the present study, we examined the effects of riluzole and gabapentin on glutamate uptake and release and glutamate-induced Ca2+ responses in primary cultures of astrocytes. Riluzole and gabapentin facilitated glutamate-induced glutamate release from astrocytes and significantly increased glutamate uptake, the latter being completely blocked by the non-selective glutamate transporter blocker DL-threo-β-benzyloxyaspartic acid (DL-TBOA). Riluzole and gabapentin also enhanced the glutamate-induced increase in intracellular Ca2+ concentrations. Some α2δ subunit ligands, pregabalin and L-isoleucine, enhanced the glutamate-induced Ca2+ response, whereas another, 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA), did not. The enhancement of glutamate-induced intracellular Ca2+ response by riluzole and gabapentin was blocked by the DL-TBOA and an inhibitor of Na+/Ca2+ exchange, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiurea (KB-R7943). Gabapentin’s enhancement of Ca2+ increase was specific to glutamate stimulation, as it was not mimicked with stimulation by ATP. These results suggest that riluzole and gabapentin enhance Na+-glutamate co-transport through glutamate transporters, induce subsequent Ca2+ influx via the reverse mode of Na+/Ca2+ exchange, and thereby facilitate Ca2+-dependent glutamate release by glutamate in astrocytes. The present study also demonstrates a novel target of gabapentinoid action in astrocytes other than α2δ subunits in neurons.

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A study comparing the actions of gabapentin and pregabalin on the electrophysiological properties of cultured DRG neurones from neonatal rats

Cited by 83 publications

References 49 publications

Gabapentin Inhibits Catecholamine Release from Adrenal Chromaffin Cells

Gabapentin Inhibits Catecholamine Release from Adrenal Chromaffin Cells

Modulation of voltage-gated Ca²⁺ channels in rat retinal ganglion cells by gabapentin

Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes

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A study comparing the actions of gabapentin and pregabalin on the electrophysiological properties of cultured DRG neurones from neonatal rats

Cited by 83 publications

References 49 publications

Gabapentin Inhibits Catecholamine Release from Adrenal Chromaffin Cells

Gabapentin Inhibits Catecholamine Release from Adrenal Chromaffin Cells

Modulation of voltage-gated Ca2+ channels in rat retinal ganglion cells by gabapentin

Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes

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Modulation of voltage-gated Ca²⁺ channels in rat retinal ganglion cells by gabapentin