Abstract
1 This study examined the action of gabapentin (gabapentin,1-(aminomethyl) cyclohexane acetic acid (Neurontin(R))) on voltage-gated calcium (Ca2+) channel influx recorded in cultured rat dorsal root ganglion (DRG) neurones.
2 Voltage-gated Ca2+ influx was monitored using both fura-2 based fluorescence Ca2+ imaging and the whole-cell patch clamp technique.
3 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 similar to25-30% in the presence of gabapentin (25 muM).
4 Gabapentin potently inhibited the peak whole-cell Ca2+ channel current (I-Ba) in a dose-dependent manner with an estimated IC50 value of 167 rim. Block was incomplete and saturated at a maximal concentration of 25 muM.
5 Inhibition was significantly decreased in the presence of the neutral amino acid L-isoleucine (25 muM) but unaffected by application of the GABA(B) antagonist, saclofen (200 muM), suggesting a direct action on the alpha(2)delta subunit of the Ca2+ channel.
6 Gabapentin inhibition was voltage-dependent, producing an similar to 7 mV hyperpolarizing shift in current voltage properties and reducing a non-inactivating component of whole-cell current activated at relatively depolarized potentials.
7 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.
8 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.
| Original language | English |
|---|---|
| Pages (from-to) | 257-265 |
| Number of pages | 8 |
| Journal | British Journal of Pharmacology |
| Volume | 135 |
| DOIs | |
| Publication status | Published - Jan 2002 |
Keywords
- gabapentin
- Ca2+ channels
- dorsal root ganglia
- patch-clamp
- fluorescence calcium imaging
- pain
- sensory neurones
- ALPHA(2)DELTA AUXILIARY SUBUNIT
- RANDOMIZED CONTROLLED TRIAL
- NEUROPATHIC PAIN
- NEOCORTICAL SLICES
- CA2+ CHANNELS
- SPINAL-CORD
- ACID
- EPILEPSY
- RELEASE
- BRAIN
Cite this
Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones. / Sutton, K. G.; Pinnock, R. D.; Lee, K.; Scott, Roderick Hamilton.
In: British Journal of Pharmacology, Vol. 135, 01.2002, p. 257-265.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones
AU - Sutton, K. G.
AU - Pinnock, R. D.
AU - Lee, K.
AU - Scott, Roderick Hamilton
PY - 2002/1
Y1 - 2002/1
N2 - 1 This study examined the action of gabapentin (gabapentin,1-(aminomethyl) cyclohexane acetic acid (Neurontin(R))) on voltage-gated calcium (Ca2+) channel influx recorded in cultured rat dorsal root ganglion (DRG) neurones.2 Voltage-gated Ca2+ influx was monitored using both fura-2 based fluorescence Ca2+ imaging and the whole-cell patch clamp technique.3 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 similar to25-30% in the presence of gabapentin (25 muM).4 Gabapentin potently inhibited the peak whole-cell Ca2+ channel current (I-Ba) in a dose-dependent manner with an estimated IC50 value of 167 rim. Block was incomplete and saturated at a maximal concentration of 25 muM.5 Inhibition was significantly decreased in the presence of the neutral amino acid L-isoleucine (25 muM) but unaffected by application of the GABA(B) antagonist, saclofen (200 muM), suggesting a direct action on the alpha(2)delta subunit of the Ca2+ channel.6 Gabapentin inhibition was voltage-dependent, producing an similar to 7 mV hyperpolarizing shift in current voltage properties and reducing a non-inactivating component of whole-cell current activated at relatively depolarized potentials.7 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.8 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.
AB - 1 This study examined the action of gabapentin (gabapentin,1-(aminomethyl) cyclohexane acetic acid (Neurontin(R))) on voltage-gated calcium (Ca2+) channel influx recorded in cultured rat dorsal root ganglion (DRG) neurones.2 Voltage-gated Ca2+ influx was monitored using both fura-2 based fluorescence Ca2+ imaging and the whole-cell patch clamp technique.3 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 similar to25-30% in the presence of gabapentin (25 muM).4 Gabapentin potently inhibited the peak whole-cell Ca2+ channel current (I-Ba) in a dose-dependent manner with an estimated IC50 value of 167 rim. Block was incomplete and saturated at a maximal concentration of 25 muM.5 Inhibition was significantly decreased in the presence of the neutral amino acid L-isoleucine (25 muM) but unaffected by application of the GABA(B) antagonist, saclofen (200 muM), suggesting a direct action on the alpha(2)delta subunit of the Ca2+ channel.6 Gabapentin inhibition was voltage-dependent, producing an similar to 7 mV hyperpolarizing shift in current voltage properties and reducing a non-inactivating component of whole-cell current activated at relatively depolarized potentials.7 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.8 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.
KW - gabapentin
KW - Ca2+ channels
KW - dorsal root ganglia
KW - patch-clamp
KW - fluorescence calcium imaging
KW - pain
KW - sensory neurones
KW - ALPHA(2)DELTA AUXILIARY SUBUNIT
KW - RANDOMIZED CONTROLLED TRIAL
KW - NEUROPATHIC PAIN
KW - NEOCORTICAL SLICES
KW - CA2+ CHANNELS
KW - SPINAL-CORD
KW - ACID
KW - EPILEPSY
KW - RELEASE
KW - BRAIN
U2 - 10.1038/sj.bjp.0704439
DO - 10.1038/sj.bjp.0704439
M3 - Article
VL - 135
SP - 257
EP - 265
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
ER -