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

Brain. 2007 Oct;130(Pt 10):2688-702. doi: 10.1093/brain/awm195. Epub 2007 Aug 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-HIV Agents / toxicity*
  • Chemokine CCL2 / metabolism
  • Cold Temperature
  • Disease Models, Animal
  • Epidermis / innervation
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiopathology
  • Gliosis / chemically induced
  • HIV Envelope Protein gp120 / toxicity*
  • Hot Temperature
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / metabolism
  • Hyperalgesia / 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*
  • Peripheral Nervous System Diseases / metabolism
  • Peripheral Nervous System Diseases / physiopathology
  • Physical Stimulation / methods
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Inhibitors / toxicity
  • Zalcitabine / toxicity*

Substances

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