The precise mechanism of action underlying the anticonvulsant effect of gabapentin is not known. Although Gabapentin is structurally related to, and was designed to mimic GABA , it does not bind to GABA receptors. Gabapentin binds preferentially to neurons in the outer layer of the rat cortex at sites that are distinct from other anticonvulsants. It is likely that gabapentin acts at an intracellular site as the maximal anticonvulsant effect is achieved 2h after an intravenous injection of gabapentin in rats. This occurs after the plasma and interstitial fluid concentrations have peaked and reflects the additional time required for intra-neural transport. Furthermore, its distinct profile of anticonvulsant activity in animal seizure models and its lack of activity at many drug binding sites associated with other antiepileptic drugs indicate that its mechanism of action is different.
The finding that gabapentin can antagonize presynaptic, voltage-gated (voltage-sensitive) calcium channels containing the alpha 2-delta (α2δ) subunit, thereby limiting neurotransmitter release, has focused attention on this mechanism as the action underlying the therapeutic effects of gabapentin in epilepsy and pain. However, gabapentin also increases the synaptic concentration of GABA, enhances GABA responses at non-synaptic sites in neuronal tissues, and reduces the release of mono-amine neurotransmitters. One of the mechanisms implicated in this effect of gabapentin is the reduction of the axon excitability measured as an amplitude change of the presynaptic fibre volley (FV) in the CA1 area of the hippocampus. This is mediated through its binding to presynaptic N-methyl-d-aspartate (NMDA) receptors. Other studies have shown that the effects of gabapentin in alleviating neuropathic pain are mediated by the descending noradrenergic system, resulting in the activation of spinal alpha2-adrenergic receptors. Gabapentin has also been shown to bind and activate the adenosine A1 receptor. The following table gives the possible target receptors for gabapentin.
|Voltage-dependent calcium channel subunit alpha-2/delta-1||inhibitor|
|Voltage-dependent calcium channel subunit alpha-2/delta-2||inhibitor|
|Voltage-dependent N-type calcium channel subunit alpha-1B||inhibitor|
|Adenosine receptor A1||agonist|
|NMDA receptor||Not Available|
|Gamma-aminobutyric acid type B receptor subunit 1||Not Available|
|Gamma-aminobutyric acid type B receptor subunit 2|
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