Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy.
A painful neuropathy is frequently observed in people living with human immunodeficiency virus type 1 (HIV-1). The HIV coat protein, glycoprotein 120 (gp120), implicated in the pathogenesis of neurological disorders associated with HIV, is capable of initiating neurotoxic cascades via an interaction with the CXCR4 and/or CCR5 chemokine receptors, which may underlie the pathogenesis of HIV-associated peripheral neuropathic pain. In order to elucidate the mechanisms underlying HIV-induced painful peripheral neuropathy, we have characterised pathological events in the peripheral and central nervous system following application of HIV-1 gp120 to the rat sciatic nerve. Perineural HIV-1 gp120 treatment induced a persistent mechanical hypersensitivity (44% decrease from baseline), but no alterations in sensitivity to thermal or cold stimuli, and thigmotactic (anxiety-like) behaviour in the open field. The mechanical hypersensitivity was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. Immunohistochemical studies reveal: decreased intraepidermal nerve fibre density, macrophage infiltration into the peripheral nerve at the site of perineural HIV-1 gp120; changes in sensory neuron phenotype including expression of activating transcription factor 3 (ATF3) in 27% of cells, caspase-3 in 25% of cells, neuropeptide Y (NPY) in 12% of cells and galanin in 13% of cells and a spinal gliosis. These novel findings suggest that this model is not only useful for the elucidation of mechanisms underlying HIV-1-related peripheral neuropathy but may prove useful for preclinical assessment of drugs for the treatment of HIV-1 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, 369 Fulham Road, London SW10 9NH, UK.
Blackbeard
Julie
J
Pheby
Timothy
T
Segerdahl
Andrew R
AR
Davies
Meirion
M
Hasnie
Fauzia
F
Hall
Susan
S
McMahon
Stephen B
SB
Rice
Andrew S C
AS
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000700:Analgesics / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015699:HIV Envelope Protein gp120; D008264:Macrophages / Q000187:drug effects; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D012585:Sciatica / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
D051700:Activating Transcription Factor 3; D000700:Analgesics; C497108:Atf3 protein, rat; D019922:GAP-43 Protein; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase; D053148:Caspase 3