Abstract
Chronic neuropathic pain is a debilitating condition that presents a significant therapeutic challenge. Unlike nociceptive pain, neuropathic pain is predominantly driven by glutamate NMDA receptors (NMDARs) and/or Ca(2+)-permeable AMPA receptors (CP-AMPARs) at synapses between primary afferent nerves and excitatory neurons in the spinal dorsal horn. The α2δ-1 protein, encoded by Cacna2d1 and historically recognized as a subunit of voltage-activated Ca(2+) channels, is the primary target of gabapentinoids, such as gabapentin and pregabalin, which are widely prescribed for neuropathic pain and epilepsy. However, gabapentinoids have minimal effects on Ca(2+) channel activity. Recent studies reveal that α2δ-1 plays a pivotal role in amplifying nociceptive input to the spinal cord in neuropathic pain. This action is mediated through its dynamic physical interactions with phosphorylated NMDARs and GluA1/GluA2 subunits via its intrinsically disordered C-terminal region. α2δ-1 not only promotes synaptic trafficking of NMDARs but also disrupts heteromeric assembly of GluA1/GluA2 subunits in the spinal dorsal horn. The central function of α2δ-1 is to elevate intracellular Ca(2+) concentrations at both presynaptic and postsynaptic sites, augmenting nociceptive transmission. Consequently, α2δ-1 serves as a dual regulator coordinating synaptic expression of NMDARs and GluA1 homomeric CP-AMPARs, a function that underlies the therapeutic actions of gabapentinoids. By inhibiting α2δ-1, gabapentinoids reduce the hyperactivity of synaptic α2δ-1-bound NMDARs and CP-AMPARs, thereby dampening the excessive excitatory synaptic transmission characteristic of neuropathic pain. These newly identified roles of α2δ-1 in orchestrating glutamatergic synaptic plasticity suggest that gabapentinoids could be repurposed for treating other neurological disorders involving dysregulated synaptic NMDARs and CP-AMPARs.