| Distal symmetrical polyneuropathy afflicts about 40% of people living with Human Immunodeficiency Virus (HIV), most of whom have measurable sensory abnormalities and on-going, paroxysmal pain. Currently two reasons are thought to induce HIV-related neuropathy. First, a disease-related DSP associated with HIV-infection itself, especially the coat protein gp120; or secondly a drug- induced DSP associated with the use of nucleoside reverse transcriptase inhibitors (NRTI), particularly the dideoxynuleosides; zalcitabine (ddC), didanosine (ddI) and stavudine (d4T), as part of highly active anti-retroviral therapy (HAART). The use of HAART has markedly increased patient survival making, painful DSP an important source of morbidity in otherwise reasonably healthy HIV-infected individuals. This limits viral suppression strategies and may precipitate discontinuation of anti-retroviral therapy. Therefore, it is important that analgesic strategies are developed to combat this pain. The exact pathogenesis of HIV-associated neuropathies is unclearDirect infection of the nervous system by HIV is thought to be unlikely. Instead, HIV appears to interact with the nervous system via binding of the external envelope protein, gp120, to the chemokine receptors CXCR4 and/or CCR5 expressed on glial cells. Such interactions can result in neurotoxocity. Previous studies indicate that HIV virus infection is able to increase the production and utilization of several cytokines, such as TNFαand IL-1β. Cerebrospinal fluid from most of the patients with AIDS has increased levels of TNFα, TNFαis involved in the development of pain shown in our previous studies of neuropathic pain induced by spinal cord injury, spinal nerve ligation, and of inflammatory pain. In order to elucidate the mechanisms underlying drug-induced neuropathy in the context of HIV infection, we have characterized pathological events in the peripheral and central nervous system following peripheral gp120 application, anti-retroviral agent, ddC (Zalcitabine) with or without the concomitant delivery of HIV-gp120 to the rat sciatic nerve (gp120+ddC). The results showed that HIV-gp120 or systemic ddC treatment alone is associated with a persistent mechanical hypersensitivity that when combined with perineural HIV-gp120 is exacerbated. We found that chemokine GFAP and TNFαare significantly expressed in the DRG and spinal cord of rats treated with perineural HIV-gp120 and/or ddC and there is a reduction in intraepidermal nerve fiber density. Furthermore, a spinal gliosis is apparent at times of peak behavior sensitivity that is exacerbated in gp120+ddC as compared to either treatment alone.Moreover, intrathecal administration of TNF siRNA or soluble TNF receptor reversed mechanical allodynia in these three models. Treatment with the glial inhibitor, pentoxifylline, is associated with delayed onset of hypersensitivity to mechanical stimuli in the gp120, ddC and gp120+ddC models and reversal of some measures of thigmotaxis.These data suggests that HIV-gp120 and ddC may have a synergistic effect on neuropathic pain. They therefore merit further investigation for the elucidation of underlying mechanisms and may provide useful evidence for preclinical assessment of drugs for the treatment of HIV-related peripheral neuropathic pain. |
