| Chronic pain is a common and debilitating consequence of human immunodefi-ciency virus （HIV）infection. The most common presentation of chronic pain inpatients infected with HIV is painful sensory neuropathy (HIV-SN), which may affectup to30%of AIDS patients. The symptoms of HIV-SN are dominated by neuropathicpain. The underlying causes of this neuropathic pain is unknown, but has beenhypothesized to involve two reasons. Firstly, HIV-infection itself, especially the coatprotein gp120; secondly, the use of nucleoside reverse transcriptase inhibitors (NRTI),particularly the dideoxynuleosides.In this study we focused on the gp120-induced neuropathic pain, and the goal wasto reveal the underlying mechanism. The main projects are as followed:1. The construction of gp120-induced neuropathic pain modelThe underlying causes of neuropathic pain are most likely not due to directinfection of the nervous system by active virus. The goal of this study was todetermine whether epineural exposure to the HIV-1envelope protein gp120couldlead to chronic neuropathic pain. Two doses of gp120or RSA control were transientlydelivered epineurally via oxidized cellulose wrapped around the rat sciatic nerve.Animals were assessed for neuropathic pain behaviors at several intervals from1–7weeks following nerve surgery. Allodynia was observed on the ipsilateral paw fromday5following gp120applications and sustained throughout the testing period,mechanical threshold reached the lowest values at2weeks after gp120application. Inthe sham group treated with RSA, rats showed no significant changes in mechanicalthreshold throughout the7-week testing period. Gp120application significantlyincreased expression of GFAP, Iba1(a marker of microglia) protein in the spinaldorsal horn. Intrathecal administration of pentoxifylline, a non-specific glial cytokineinhibitor significantly reversed the mechanical allodynia in the model.2. The role of TNFα in gp120-induced neuropathic painPrevious study demonstrated that HIV infection may upregulate some cytokines,such as TNFα. Therefore, in this study, we try to determine whether TNFα is involved in the gp120-induced neuropathic pain. The results showed that: compared to thesham group, gp120application upregulated TNFα both in protein and mRNA level;TNFα was released by microglia and astrocytes. Furthermore, knockdown ofTNFα with siRNA or recombinant soluble TNF receptor reversed mechanicalallodynia induced by gp120application. These findings indicate that glial TNFα inthe spinal cord regulates neuropathic pain induced by HIV gp120.3. The role of reactive oxygen species (ROS) in gp120induced neuropathic painand crosstalk between ROS and TNFαROS has been reported to play an important role in various acute and chronic painmodels, however, nobody reports its role in the gp120induced neuropathic pain. Inthis study, the findings show that: compared to the sham group, the SOD2activity inthe ipsilateral spinal dorsal horn was decreased by HIV gp120application, andnitrated SOD2was increased; ROS scavenger PBN and MitoTEMPOL reversedmechanical allodynia induced by gp120application; intrathecal administration ofMitoTEMPOL reversed SOD2activity and the expression of TNFα; knockdown ofTNFα with siRNA or recombinant soluble TNF receptor reversed SOD2activity.These findings suggest the HIV gp120-induced neuropathic pain model work well,and both TNFα and ROS regulate the neuropathic pain. Furthermore TNFα and ROSmay have a synergistic effect on neuropathic pain induced by HIV gp120application.While the mechanisms underlying HIV-related neuropathic pain are poorlyunderstood, the results of the current investigation provide an important insight intothe pathogenesis of chronic pain. Furthermore, the discovery of this study opens anew therapeutic strategy for the development of agents for the treatment ofHIV-related peripheral neuropathic pain. |
