Mechanism of Action of Gabapentin
Gabapentin primarily exerts its therapeutic effects by binding to the α2δ subunit of voltage-gated calcium channels, though the precise relationship between this binding and its clinical effects remains incompletely understood. 1
Primary Mechanism
- Gabapentin binds with high affinity to the α2δ subunit (specifically α2δ-1 and α2δ-2) of voltage-activated calcium channels, which is considered its primary mechanism of action 2, 1
- This binding reduces calcium influx and decreases synaptic neurotransmitter release into hyperexcited neurons 2
- The drug shows greater affinity for α2δ-1 than α2δ-2 and no affinity for the α2δ-3 subunit 2
Important Structural Relationship Without GABA Activity
- Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but does NOT act through GABA mechanisms 1
- It does NOT act as an agonist at GABAA or GABAB receptors 2
- It has no effect on GABA binding, uptake, or degradation 2, 1
- Despite structural similarity to GABA, gabapentin penetrates the CNS while GABA does not cross the blood-brain barrier 3
Time-Dependent Effects on Calcium Channels
- Gabapentin requires chronic exposure (17-20 hours) rather than acute administration to effectively inhibit calcium currents 4
- The drug acts primarily at an intracellular location, requiring cellular uptake 4
- Chronic gabapentin disrupts the trafficking of α2δ subunits and calcium channels to the cell surface 4
Additional Proposed Mechanisms
- Gabapentin is a potent activator of KCNQ3 and KCNQ5 potassium channels (EC50 = 5.3 nM for KCNQ3 and 1.9 nM for KCNQ5), which may contribute to its anticonvulsant and analgesic effects 5
- The drug may increase GABA concentration and synthesis rate in brain tissue, though this does not involve direct GABA receptor activity 2, 6
- Gabapentin reduces the release of several monoamine neurotransmitters 6
- It crosses membrane barriers via a specific amino acid transporter (system L), competing with leucine, isoleucine, valine, and phenylalanine 6
Clinical Implications
- The mechanism prevents allodynia and hyperalgesia in animal models, making it particularly effective for neuropathic pain 7, 8
- The drug's lack of GABA-related activity explains why it has no effect on GABA binding, uptake, or degradation, distinguishing it from other anticonvulsants 1
- Gabapentin is not appreciably metabolized in humans, with all pharmacological actions due to the parent compound 1
Common Pitfall
Do not assume gabapentin works through GABA mechanisms despite its structural similarity to GABA—this is a common misconception that can lead to incorrect expectations about drug interactions and effects 2, 1