The anticonvulsant gabapentin (neurontin) does not act through gamma-aminobutyric acid-B receptors
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The anticonvulsant gabapentin (neurontin) does not act through gamma-aminobutyric acid-B receptors. / Jensen, Anders A.; Mosbacher, Johannes; Elg, Susanne; Lingenhoehl, Kurt; Lohmann, Tania; Johansen, Tommy N; Abrahamsen, Bjarke; Mattsson, Jan; Lehmann, Anders; Bettler, Bernhard; Bräuner-Osborne, Hans.
In: Molecular Pharmacology, Vol. 61, No. 6, 2002, p. 1377-84.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - The anticonvulsant gabapentin (neurontin) does not act through gamma-aminobutyric acid-B receptors
AU - Jensen, Anders A.
AU - Mosbacher, Johannes
AU - Elg, Susanne
AU - Lingenhoehl, Kurt
AU - Lohmann, Tania
AU - Johansen, Tommy N
AU - Abrahamsen, Bjarke
AU - Mattsson, Jan
AU - Lehmann, Anders
AU - Bettler, Bernhard
AU - Bräuner-Osborne, Hans
PY - 2002
Y1 - 2002
N2 - The actions of the anticonvulsant gabapentin [1-(aminomethyl)cyclohexaneacetic acid, Neurontin] have been somewhat enigmatic until recently, when it was claimed to be a gamma-aminobutyric acid-B (GABA(B)) receptor agonist acting exclusively at a heterodimeric complex containing the GABA(B(1a)) splice variant (Mol Pharmacol 2001;59:144-152). In this study, we have investigated the effects of gabapentin on recombinant GABA(B(1a)) and GABA(B(1b)) receptors coexpressed with GABA(B(2)) in five different functional recombinant assays, its ability to inhibit [(3)H]GABA binding in a GABA(B) receptor-selective binding assay using rat synaptic membranes, and its ability to inhibit transient lower esophageal sphincter relaxations in Labrador retriever dogs. Up to a concentration of 1 mM, gabapentin displayed no agonistic effects on either the GABA(B(1a,2)) or the GABA(B(1b,2)) heterodimer, when these were expressed in Xenopus laevis oocytes or mammalian cells and assayed by means of electrophysiology, calcium mobilization, inositol phosphate, and fluorometry assays. Gabapentin did not displace [(3)H]GABA from GABA(B) receptor sites in rat synaptic membranes. Finally, in contrast to the classic GABA(B) receptor agonist baclofen, gabapentin was unable to inhibit transient lower esophageal sphincter relaxations in dogs. Because of high levels of GABA(B(1a)) in the canine nodose ganglion, this finding indirectly supports the inactivity of gabapentin on the GABA(B(1a,2)) heterodimer demonstrated in various in vitro assays. In light of these results, we find it highly questionable that gabapentin is a GABA(B) receptor agonist. Hence, the anticonvulsive effects of the compound have to arise from GABA(B) receptor-independent mechanisms. This also implies that the first GABA(B) receptor splice variant-selective ligand remains to be discovered.
AB - The actions of the anticonvulsant gabapentin [1-(aminomethyl)cyclohexaneacetic acid, Neurontin] have been somewhat enigmatic until recently, when it was claimed to be a gamma-aminobutyric acid-B (GABA(B)) receptor agonist acting exclusively at a heterodimeric complex containing the GABA(B(1a)) splice variant (Mol Pharmacol 2001;59:144-152). In this study, we have investigated the effects of gabapentin on recombinant GABA(B(1a)) and GABA(B(1b)) receptors coexpressed with GABA(B(2)) in five different functional recombinant assays, its ability to inhibit [(3)H]GABA binding in a GABA(B) receptor-selective binding assay using rat synaptic membranes, and its ability to inhibit transient lower esophageal sphincter relaxations in Labrador retriever dogs. Up to a concentration of 1 mM, gabapentin displayed no agonistic effects on either the GABA(B(1a,2)) or the GABA(B(1b,2)) heterodimer, when these were expressed in Xenopus laevis oocytes or mammalian cells and assayed by means of electrophysiology, calcium mobilization, inositol phosphate, and fluorometry assays. Gabapentin did not displace [(3)H]GABA from GABA(B) receptor sites in rat synaptic membranes. Finally, in contrast to the classic GABA(B) receptor agonist baclofen, gabapentin was unable to inhibit transient lower esophageal sphincter relaxations in dogs. Because of high levels of GABA(B(1a)) in the canine nodose ganglion, this finding indirectly supports the inactivity of gabapentin on the GABA(B(1a,2)) heterodimer demonstrated in various in vitro assays. In light of these results, we find it highly questionable that gabapentin is a GABA(B) receptor agonist. Hence, the anticonvulsive effects of the compound have to arise from GABA(B) receptor-independent mechanisms. This also implies that the first GABA(B) receptor splice variant-selective ligand remains to be discovered.
KW - Acetic Acids
KW - Amines
KW - Animals
KW - Anticonvulsants
KW - Cells, Cultured
KW - Cyclohexanecarboxylic Acids
KW - Dogs
KW - Esophagogastric Junction
KW - Humans
KW - Models, Animal
KW - Oocytes
KW - Rats
KW - Receptors, GABA-B
KW - Recombinant Proteins
KW - Synaptic Membranes
KW - Xenopus laevis
KW - gamma-Aminobutyric Acid
U2 - 10.1124/mol.61.6.1377
DO - 10.1124/mol.61.6.1377
M3 - Journal article
C2 - 12021399
VL - 61
SP - 1377
EP - 1384
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 6
ER -
ID: 38485188