Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain.

Abstract

A distal symmetrical sensory peripheral neuropathy is frequently observed in people living with Human Immunodeficiency Virus Type 1 (HIV-1). This neuropathy can be associated with viral infection alone, probably involving a role for the envelope glycoprotein gp120; or a drug-induced toxic neuropathy associated with the use of nucleoside analogue reverse transcriptase inhibitors as a component of highly active anti-retroviral therapy. 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 systemic treatment with the anti-retroviral agent, ddC (Zalcitabine) with or without the concomitant delivery of HIV-gp120 to the rat sciatic nerve (gp120+ddC). Systemic ddC treatment alone is associated with a persistent mechanical hypersensitivity (33% decrease in limb withdrawal threshold) that when combined with perineural HIV-gp120 is exacerbated (48% decrease in threshold) and both treatments result in thigmotactic (anxiety-like) behaviour. Immunohistochemical studies revealed little ddC-associated alteration in DRG phenotype, as compared with known changes following perineural HIV-gp120. However, the chemokine CCL2 is significantly expressed in the DRG of rats treated with perineural HIV-gp120 and/or ddC and there is a reduction in intraepidermal nerve fibre density, comparable to that seen in herpes zoster infection. Moreover, a spinal gliosis is apparent at times of peak behavioural sensitivity that is exacerbated in gp120+ddC as compared to either treatment alone. Treatment with the microglial inhibitor, minocycline, is associated with delayed onset of hypersensitivity to mechanical stimuli in the gp120+ddC model and reversal of some measures of thigmotaxis. Finally, the hypersensitivity to mechanical stimuli was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. These data suggests that both neuropathic pain models display many features of HIV- and anti-retroviral-related peripheral neuropathy. They therefore merit further investigation for the elucidation of underlying mechanisms and may prove useful for preclinical assessment of drugs for the treatment of HIV-related peripheral neuropathic pain.

• Authors: Victoria C J Wallace, Julie Blackbeard, Andrew R Segerdahl, Fauzia Hasnie, Timothy Pheby, Stephen B McMahon, Andrew S C Rice
• Journal: Brain : a journal of neurology (Brain) Vol. 130 Issue Pt 10 Pg. 2688-702 (Oct 2007) ISSN: 1460-2156 [Electronic] England
• PMID: 17761732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Anti-HIV Agents
• Ccl2 protein, rat
• Chemokine CCL2
• HIV Envelope Protein gp120
• Nerve Tissue Proteins
• Reverse Transcriptase Inhibitors
• Zalcitabine
• Minocycline

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Anti-HIV Agents (toxicity)
• Chemokine CCL2 (metabolism)
• Cold Temperature
• Disease Models, Animal
• Epidermis (innervation)
• Ganglia, Spinal (drug effects, physiopathology)
• Gliosis (chemically induced)
• HIV Envelope Protein gp120 (toxicity)
• Hot Temperature
• Hyperalgesia (chemically induced, metabolism, physiopathology)
• Male
• Minocycline (pharmacology)
• Motor Activity (drug effects)
• Nerve Fibers (pathology)
• Nerve Tissue Proteins (metabolism)
• Pain Measurement (methods)
• Pain Threshold (drug effects)
• Peripheral Nervous System Diseases (chemically induced, metabolism, physiopathology)
• Physical Stimulation (methods)
• Rats
• Rats, Wistar
• Reverse Transcriptase Inhibitors (toxicity)
• Zalcitabine (toxicity)