Calcium Channel α2δ1, the Target of Gabapentinoids, Interacts with NMDA Receptor

To the Editor:

Gabapentinoids, including gabapentin and pregabalin, bind to the α2δ1 subunit of calcium channel (α2δ1) to relieve neuropathic pain¹. Although gabapentinoids are among the most effective medications to treat chronic neuropathic pain², their use in managing postoperative acute pain has been controversial. A recent meta-analysis of 281 randomized controlled trials by Verret et al. shows that gabapentinoids do not provide clinically significant analgesic effect for postoperative acute pain³. It would be of great interest to discuss the potential mechanism behind why gabapentinoids have limited effect in postoperative acute pain.

α2δ1 is constitutively expressed in dorsal root ganglion (DRG). Its expression is greatly induced after nerve injury⁴, and the upregulated α2δ1 is transported from DRG sensory neurons to spinal cord⁵. Because α2δ1 is a subunit of the voltage-activated Ca²⁺ channel complex, it has been postulated that gabapentinoids work through modulating Ca²⁺ channels. However, gabapentinoids do not alter the activity of Ca²⁺ channels, suggesting that the effect of gabapentinoids in treating pain is independent from the regulation of Ca²⁺ channel activity^6,7.

Chen et al. recently discovered a novel mechanism through which gabapentinoids relieve neuropathic pain⁷. They found that α2δ1 binds to N-methyl-D-aspartate (NMDA) receptor in both rodent and human to enhance its activity in spinal cord after nerve injury, and gabapentin prevents α2δ1-mediated NMDA receptor (NMDAR) hyperactivity⁷. Importantly, baseline α2δ1 does not facilitate spinal cord NMDAR activity, but the upregulated α2δ1, like after nerve injury, is associated with the enhanced spinal cord NMDAR activity and neuropathic pain behavior⁷. Notably, α2δ1 does not contribute to the acute pain immediately after nerve injury. In preclinical models, it takes up to 2 days for α2δ1 to be fully upregulated after nerve injury⁴, and knocking down α2δ1 has no effect on neuropathic pain behavior within the first 2 days after nerve injury, even though it attenuates pain behavior at later time points⁷. Taken together, Chen et al. have revealed a new mechanism in which gabapentinoids reduce neuropathic pain by inhibiting spinal cord NMDAR hyperactivity mediated by upregulated α2δ1.

The role of NMDAR in many pain conditions, including postoperative pain, has been well recognized⁸. The interaction between α2δ1 and NMDAR explains why gabapentinoids are effective in treating chronic neuropathic pain, but not postoperative acute pain. In chronic neuropathic pain, α2δ1 is upregulated to enhance NMDAR activity in spinal cord to produce neuropathic pain, and gabapentinoids prevent the interaction between the upregulated α2δ1 and NMDAR to relieve neuropathic pain. In healthy uninjured state, the interaction between baseline α2δ1 and NMDAR is minimal, and gabapentinoids have no influence on baseline NMDAR activity in spinal cord. It takes time for α2δ1 to be fully induced after injury, so during the perioperative period it is likely that α2δ1 remains at or near baseline level with minimal interaction with NMDAR. As the result, perioperative gabapentinoids, especially administered before surgical injury, have limited effects on spinal cord NMDAR activity to reduce acute pain immediately after surgery. Furthermore, as gabapentin treatment does not prevent α2δ1 upregulation after nerve injury⁵, it is also unlikely that perioperative gabapentinoids can prevent chronic postoperative pain, consistent with meta-analysis from Verret et al³.

In conclusion, gabapentinoids disrupt the interaction between the upregulated α2δ1 and NMDAR to inhibit spinal cord NMDAR hyperactivity in treating chronic neuropathic pain. As the acute postoperative pain precedes injury-induced α2δ1 upregulation, and gabapentinoids have no effect on NMDAR without α2δ1 upregulation, perioperative gabapentinoids do not have clinically significant impact on postoperative pain.