The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions

alpha 2 delta-1, commonly known as a voltage-activated Ca2+ channel subunit, is a binding site of gabapentinoids used to treat neuropathic pain and epilepsy. However, it is unclear how alpha 2 delta-1 contributes to neuropathic pain and gabapentinoid actions. Here, we show that Cacna2d1 overexpression potentiates presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons to cause pain hypersensitivity. Conversely, Cacna2d1 knockdown or ablation normalizes synaptic NMDAR activity increased by nerve injury. alpha 2 delta-1 forms a heteromeric complex with NMDARs in rodent and human spinal cords. The alpha 2 delta-1-NMDAR interaction predominantly occurs through the C terminus of alpha 2 delta-1 and promotes surface trafficking and synaptic targeting of NMDARs. Gabapentin or an alpha 2 delta-1 C terminus-interfering peptide normalizes NMDAR synaptic targeting and activity increased by nerve injury. Thus, alpha 2 delta-1 is an NMDAR-interacting protein that increases NMDAR synaptic delivery in neuropathic pain. Gabapentinoids reduce neuropathic pain by inhibiting forward trafficking of alpha 2 delta-1-NMDAR complexes.