Gabapentin inhibits high‐threshold calcium channel currents in cultured rat dorsal root ganglion neurones
KG Sutton, DJ Martin, RD Pinnock… - British journal of …, 2002 - Wiley Online Library
KG Sutton, DJ Martin, RD Pinnock, K Lee, RH Scott
British journal of pharmacology, 2002•Wiley Online LibraryThis study examined the action of gabapentin (gabapentin, 1‐(aminomethyl) cyclohexane
acetic acid (Neurontin®)) on voltage‐gated calcium (Ca2+) channel influx recorded in
cultured rat dorsal root ganglion (DRG) neurones. Voltage‐gated Ca2+ influx was monitored
using both fura‐2 based fluorescence Ca2+ imaging and the whole‐cell patch clamp
technique. Imaging of intracellular Ca2+ transients revealed that gabapentin inhibited KCl
(30 mm)‐evoked voltage‐dependent Ca2+ influx. Both the duration for 50% of the maximum …
acetic acid (Neurontin®)) on voltage‐gated calcium (Ca2+) channel influx recorded in
cultured rat dorsal root ganglion (DRG) neurones. Voltage‐gated Ca2+ influx was monitored
using both fura‐2 based fluorescence Ca2+ imaging and the whole‐cell patch clamp
technique. Imaging of intracellular Ca2+ transients revealed that gabapentin inhibited KCl
(30 mm)‐evoked voltage‐dependent Ca2+ influx. Both the duration for 50% of the maximum …
- This study examined the action of gabapentin (gabapentin,1‐(aminomethyl) cyclohexane acetic acid (Neurontin®)) on voltage‐gated calcium (Ca2+) channel influx recorded in cultured rat dorsal root ganglion (DRG) neurones.
- Voltage‐gated Ca2+ influx was monitored using both fura‐2 based fluorescence Ca2+ imaging and the whole‐cell patch clamp technique.
- Imaging of intracellular Ca2+ transients revealed that gabapentin inhibited KCl (30 mM)‐evoked voltage‐dependent Ca2+ influx. Both the duration for 50% of the maximum response (W50) and total Ca2+ influx were significantly reduced by ∼25‐30% in the presence of gabapentin (25 μM).
- Gabapentin potently inhibited the peak whole‐cell Ca2+ channel current (IBa) in a dose‐dependent manner with an estimated IC50 value of 167 nM. Block was incomplete and saturated at a maximal concentration of 25 μM.
- Inhibition was significantly decreased in the presence of the neutral amino acid L‐isoleucine (25 μM) but unaffected by application of the GABAB antagonist, saclofen (200 μM), suggesting a direct action on the α2δ subunit of the Ca2+ channel.
- Gabapentin inhibition was voltage‐dependent, producing an ∼7 mV hyperpolarizing shift in current voltage properties and reducing a non‐inactivating component of whole‐cell current activated at relatively depolarized potentials.
- The use of specific Ca2+ channel antagonists revealed a mixed pharmacology of the gabapentin‐sensitive current (N‐, L‐ and P/Q‐type), which is dominated by N‐type current.
- The present study is the first to demonstrate that gabapentin directly mediates inhibition of voltage‐gated Ca2+ influx in DRG neurones, providing a potential means for gabapentin to effectively mediate spinal anti‐nociception.
British Journal of Pharmacology (2002) 135, 257–265; doi:10.1038/sj.bjp.0704439
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