HIV-1 gp120 Induces Nociceptive Hypersensitivity via α2δ-1-Bound NMDA Receptors at Primary Afferent→Excitatory Neuron Synapses.

Human immunodeficiency virus 1 (HIV-1) infection often results in sensory neuropathy, with >60% of affected individuals developing chronic pain. Although viral proteins such as glycoprotein 120 (gp120) contribute to neuronal injury and pain hypersensitivity, their specific effects on nociceptive signaling remain unclear. Hyperactivity of N-methyl-d-aspartate receptor (NMDAR) in the spinal dorsal horn is a hallmark of neuropathic pain. Here, we determined how gp120 affects synaptic NMDAR activity in spinal excitatory and inhibitory neurons in male and female mice. Intrathecal gp120 enhanced expression of α2δ-1 and GluN1 in the dorsal root ganglion (DRG) and spinal cord. Gp120 also increased α2δ-1-GluN1 interaction and their synaptic trafficking in the spinal cord. Functionally, gp120 induced hyperactivity of presynaptic NMDARs on primary afferent terminals and postsynaptic NMDARs in vesicular glutamate transporter 2-expressing excitatory, but not vesicular GABA/glycine transporter-expressing inhibitory, dorsal horn neurons. Importantly, gp120-induced hyperactivity of both presynaptic and postsynaptic NMDARs was eliminated by the α2δ-1 inhibitory ligand gabapentin or by an α2δ-1 C-terminal peptide that disrupts α2δ-1-NMDAR interactions. Correspondingly, treatment with the NMDAR antagonist, gabapentin, or α2δ-1 C-terminal peptide consistently reversed gp120-induced persistent nociceptive hypersensitivity. Furthermore, genetic deletion of Cacna2d1 or selective ablation of GluN1 in DRG neurons significantly attenuated gp120-induced nociceptive hypersensitivity. Together, these findings indicate that gp120 drives nociceptive hypersensitivity by augmenting presynaptic and postsynaptic activity of α2δ-1-bound NMDARs, thereby amplifying nociceptive transmission from primary afferents to spinal excitatory neurons. Targeting α2δ-1-associated NMDARs may therefore represent a promising therapeutic approach for HIV-associated chronic neuropathic pain.