title: Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy.
abstract: 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.
authors: 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.
authors: Victoria C J
authors: VC
authors: Wallace
authors: Julie
authors: J
authors: Blackbeard
authors: Timothy
authors: T
authors: Pheby
authors: Andrew R
authors: AR
authors: Segerdahl
authors: Meirion
authors: M
authors: Davies
authors: Fauzia
authors: F
authors: Hasnie
authors: Susan
authors: S
authors: Hall
authors: Stephen B
authors: SB
authors: McMahon
authors: Andrew S C
authors: AS
authors: Rice
mesh_terms: 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
chemical_list: 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