Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain.
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.
Wallace
Victoria C J
VC
Pain Research Group, Department of Anaesthetics Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London SW10 9NH, UK.
Blackbeard
Julie
J
Segerdahl
Andrew R
AR
Hasnie
Fauzia
F
Pheby
Timothy
T
McMahon
Stephen B
SB
Rice
Andrew S C
AS
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000633:toxicity*; D018932:Chemokine CCL2 / Q000378:metabolism; D003080:Cold Temperature; D004195:Disease Models, Animal; D004817:Epidermis / Q000294:innervation; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology; D005911:Gliosis / Q000139:chemically induced; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008911:Minocycline / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009412:Nerve Fibers / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity; D016047:Zalcitabine / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D015699:HIV Envelope Protein gp120; D009419:Nerve Tissue Proteins; D018894:Reverse Transcriptase Inhibitors; D016047:Zalcitabine; D008911:Minocycline