Background:  Pedal pain dominates the symptomatology of HIV-associated sensory neuropathy, which is now recognized as the most common neurological complication of HIV infection. The neuropathic pain is often so severe that it interferes with walking and sleep. Little attention has so far been devoted to exploring the pathogenesis of this pain, which currently has no effective treatment. Distal C-fiber loss is a characteristic feature of HIV-associated sensory neuropathy, and the extent of this loss correlates with the degree of pain. We hypothesize that this may be because gp120, released by HIV-infected macrophages in dorsal root ganglia, excites and preferentailly injures nociceptive dorsal root ganglia neurons with subsequent dying back of their axons.

Methods:  Dissociated E15 rat embryonic dorsal root ganglia cultures were exposed to varying doses of gp120-MN or vehicle control. The outcome measures of gp120 neurotoxicity used were neuronal apoptosis and axonal degeneration. In the apoptosis experiments, the cultures were fixed after 36 hours of incubation, and were triple immunofluorescent-labeled for CGRP (a marker for nociceptive neurons), bIII-tubulin (a neuronal marker) and TUNEL. In the axonal degeneration experiments, the cultures were fixed after 24 hours of exposure and then immunostained for CGRP and ßIII-tubulin. The average total neuritic length per neuron was then measured using a digital image analysis system and unbiased stereological methods. Finally, to look for evidence of excitation of nociceptive neruons by gp120, dissociated dorsal root ganglia cultures were exposed to varying doses of gp120-MN or control for 30 minutes in the presence or absence of anti-CXCR4 blocking antibodies (12G5 clone). The supernatants were then harvested and their content of CGRP quantified by ELISA.

Results:  Gp120 in picomolar doses was neurotoxic to nociceptive dorsal root ganglia neurons, as suggested by dose-dependent apoptosis of CGRP-positive neurons and “dying back” of their axons. The nociceptive dorsal root ganglia neuronal population seemed particularly vulnerable to gp120 neurotoxicity as CGRP-negative neurons were largely unaffected. Gp120-MN and SDF-1 (a CXCR4 ligand) each stimulated extracellular release of CGRP from dorsal root ganglia cultures, and in both cases, this release was ameliorated by CXCR4 blocking antibodies.

Conclusions:  Our findings suggest that gp120, by exciting and preferentially injuring dorsal root ganglia nociceptive neurons, may contribute to the neuropathic pain and distal C-fiber loss that characterize HIV-sensory neuropathy. 

Keywords: pain; HIV neuropathy; gp120