Gabapentinoids, such as gabapentin and pregabalin, while structurally similar to GABA, do not act as GABA agonists nor increase GABA levels. Instead, they target the alpha 2 delta-1 (A2delta-1) subunits of voltage-gated calcium channels (VGCCs), primarily in the dorsal horn of the spinal cord. By disrupting these subunits, gabapentinoids reduce the stability of VGCCs on the cell surface, leading to less calcium influx and a decrease in neurotransmitter (like glutamate) release during nerve signal transmission.
This action is particularly beneficial in treating neuropathic pain where damaged neurons overly express VGCCs, leading to excessive calcium entry and pain signal amplification. However, gabapentinoids are less effective for acute pain, such as post-surgical pain, because their mechanism doesn't directly counteract the typical pathways involved in acute pain responses. Additionally, potential effects on other pain pathways involving NMDA receptors, sodium currents, and neurotransmitters like serotonin and norepinephrine might contribute to their overall pain-modulating properties but are not the primary mode of action for these drugs.
| Agent class | Molecular target | Effect and caveat |
|---|---|---|
| Opioids | Mu, kappa and delta opioid receptors (G protein-coupled) | Close calcium channels and open potassium channels, hyperpolarizing neurons and reducing neurotransmitter release in the midbrain, pons, medulla and spinal cord |
| Local anesthetics | Sodium channels in nerve axons | Work only on open or inactive channels and only in the un-ionized form, so effectiveness falls in acidic inflamed or infected tissue; most effective on small Aδ and C fibers |
| Magnesium | NMDA receptors in the dorsal horn | Maintains the natural magnesium block during high glutamate activity; also relaxes muscle by lowering cytoplasmic calcium |
| Alpha-2 agonists | Alpha-2 receptors in the dorsal horn and presynaptic terminals | Enhance endogenous opioid release from interneurons and lower catecholamine release and peripheral sympathetic activity |
| Ketamine | NMDA-type glutamate receptors in the central nervous system and dorsal horn | Blunts the “windup” intensification of pain; also inhibits serotonin and norepinephrine reuptake and has opioid agonist properties |
| Antidepressants (tricyclics, SNRIs) | Presynaptic reuptake of norepinephrine and serotonin | Raise neurotransmitter availability in the dorsal horn to suppress pain transmission; SSRIs are generally less effective for pain |
| Gabapentinoids | α2δ-1 subunits of voltage-gated calcium channels in the dorsal horn | Reduce calcium influx and glutamate release; particularly useful in neuropathic pain but less effective for acute post-surgical pain |
