HIV-1 gp120 induces nociceptive hypersensitivity via α2δ-1–bound NMDA receptors at primary afferent–excitatory neuron synapses

HIV-1 infection often results in sensory neuropathy, with more than 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 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 (VGluT2)–expressing excitatory, but not vesicular GABA/glycine transporter (VGAT)–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 dorsal root ganglion 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. Significance Statement HIV-associated chronic pain affects a large proportion of people living with HIV and remains challenging to treat. This study reveals how the HIV viral protein gp120 augments transmission from peripheral nerves to spinal cord neurons to produce persistent pain. We show that gp120 strengthens the interaction between the α2δ-1 protein and NMDA receptors in the spinal cord. Remarkably, gp120 selectively potentiates synaptic NMDA receptor activity in spinal excitatory, but not inhibitory, neurons, leading to heightened nociceptive sensitivity. Importantly, blocking α2δ-1 or disrupting its coupling with NMDA receptors reverses these effects and alleviates pain-like behaviors in animal models. These findings uncover a molecular mechanism underlying gp120-induced central sensitization and identify a potential therapeutic target for chronic pain in people with HIV.