HIV-1 gp120 induces neuropathic pain via α2δ-1-bound NMDA receptors at spinal excitatory synapses

HIV-1 infection frequently leads to sensory neuropathy and chronic pain in over 60% of affected individuals, significantly impacting quality of life. While viral proteins like glycoprotein 120 (gp120) are known contributors to neuronal injury and pain, their precise mechanisms in nociceptive signaling have been unclear. Hyperactivity of the N-methyl-D-aspartate receptor (NMDAR) in the spinal dorsal horn is a recognized hallmark of neuropathic pain, suggesting a potential pathway for gp120's effects.

Researchers investigated how gp120 affects synaptic NMDAR activity in spinal excitatory and inhibitory neurons using male and female mice. Intrathecal gp120 was administered to induce nociceptive hypersensitivity. They then assessed expression of α2δ-1 and GluN1 in dorsal root ganglia and spinal cord, along with α2δ-1-GluN1 interaction and synaptic trafficking. Functional NMDAR activity was measured in VGluT2-expressing excitatory and VGAT-expressing inhibitory dorsal horn neurons. Interventions included the α2δ-1 inhibitory ligand gabapentin or an α2δ-1 C-terminal peptide to disrupt α2δ-1-NMDAR interactions, as well as genetic deletion of Cacna2d1 or selective GluN1 ablation in DRG neurons.

Intrathecal gp120 significantly enhanced the expression of α2δ-1 and GluN1 in both the dorsal root ganglion and spinal cord. This was accompanied by an increase in α2δ-1-GluN1 interaction and their synaptic trafficking within the spinal cord. Functionally, gp120 induced hyperactivity of both presynaptic NMDARs on primary afferent terminals and postsynaptic NMDARs in VGluT2-expressing excitatory dorsal horn neurons. Importantly, this hyperactivity was not observed in VGAT-expressing inhibitory neurons. > The gp120-induced hyperactivity of both presynaptic and postsynaptic NMDARs was completely eliminated by treatment with the α2δ-1 inhibitory ligand gabapentin or by an α2δ-1 C-terminal peptide designed to disrupt α2δ-1-NMDAR interactions. Correspondingly, these treatments 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, confirming the critical role of this pathway.