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Brain Advance Access originally published online on August 30, 2007
Brain 2007 130(10):2688-2702; doi:10.1093/brain/awm195
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Victoria C. J. Wallace1, Julie Blackbeard1, Andrew R. Segerdahl1, Fauzia Hasnie1, Timothy Pheby1, Stephen B. McMahon2 and Andrew S. C. Rice1

1Pain Research Group, Department of Anaesthetics Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London SW10 9NH and 2Neurorestoration Group, Wolfson CARD, Kings College London, Guy's Hospital Campus, London SE1 1UL, UK

Correspondence to: Dr Andrew S.C. Rice, Pain Research Group, Department of Anaesthetics, Imperial College London, Chelsea and Westminster Hospital Campus, 369 Fulham Road, London SW10 9NH, UK E-mail: a.rice{at}imperial.ac.uk

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.

Key Words: HIV; anti-retroviral drugs; neuropathy; DRG; microglia

Abbreviations: AIDS, Acquired Immunodeficiency Syndrome; ANOVA, Analysis of Variance; gp120, Glycoprotein 120; DRG, dorsal root ganglion; DSP, distal symmetrical polyneuropathy; CB, cannabinoid; HIV-1, Human Immunodeficiency Virus Type 1; NPY, neuropeptide Y; ATF3, activating transcription factor 3; NF-200, neurofilament 200 kDa; GFAP, Glial fibrillary acidic protein; PB, phosphate buffer; PBS, phosphate-buffered saline; OCT, optimum cryostat temperature; RSA, rat serum albumin; gvF, graded von Frey filaments; evF, electronic von Frey device; VZV, Varicella Zoster Virus.

Received March 6, 2007. Revised July 5, 2007. Accepted July 27, 2007.


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