Mechanism of Action of Pregabalin
Pregabalin binds with high affinity to the α₂δ subunit (specifically α₂δ-1 and α₂δ-2) of voltage-gated calcium channels in the central nervous system, reducing calcium influx at nerve terminals and thereby decreasing the release of excitatory neurotransmitters from hyperexcited neurons. 1
Primary Binding Target
- Pregabalin is a potent and selective ligand for the α₂δ-1 and α₂δ-2 subunits of voltage-gated calcium channels, with no significant activity at 38 other widely studied receptors and ion channels. 2
- The binding changes the conformation of these calcium channels, specifically reducing calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord and other CNS regions. 1, 3
- This mechanism only modulates neurotransmitter release in "hyperexcited" neurons, restoring them to a normal physiological state rather than affecting all neuronal activity. 3
Effects on Neurotransmitter Release
- By reducing calcium influx, pregabalin decreases the release of multiple excitatory neurotransmitters including glutamate, norepinephrine, serotonin, dopamine, substance P, and calcitonin gene-related peptide. 4, 5
- The reduction in calcium availability impairs vesicle fusion with the presynaptic membrane, thereby inhibiting exocytosis of neurotransmitters. 6
- Evidence suggests pregabalin's anti-nociceptive effects may also involve interactions with descending noradrenergic and serotonergic pathways from the brainstem that modulate pain transmission in the spinal cord. 1
Lack of Direct GABA Activity
- Despite being a structural derivative of γ-aminobutyric acid (GABA), pregabalin does not bind directly to GABA_A, GABA_B, or benzodiazepine receptors and does not augment GABA_A responses in cultured neurons. 1
- Pregabalin does not alter acute GABA concentration, uptake, or degradation in the brain. 1
- With prolonged application in cultured neurons, pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport, but this is not the primary mechanism of action. 1
Additional Mechanistic Insights
- Pregabalin may inhibit synaptogenesis of excitatory neurons formed in response to chronic stress or anxiety, or more acutely inhibit the trafficking of calcium channels to the plasma membrane. 6
- The drug is inactive at opiate receptors, does not block sodium channels, does not alter cyclooxygenase enzyme activity, and does not inhibit monoamine reuptake. 1
- Structure-activity relationship studies demonstrate that the affinity of ligands for the α₂δ-1 protein directly correlates with their potency in animal models, and pregabalin's anxiolytic activity is lost in transgenic mice with specific point mutations in this protein. 6