title: A clinically relevant rodent model of the HIV antiretroviral drug stavudine induced painful peripheral neuropathy.
abstract: HIV-associated sensory neuropathy is the most frequent manifestation of HIV disease, afflicting 40-50% of patients whose HIV disease is otherwise controlled by antiretroviral therapy. It often presents with significant neuropathic pain and is consistently associated with previous exposure to nucleoside reverse transcriptase inhibitors including stavudine (d4T), which is widely used in resource-limited settings. Here we investigated complex pain-related behaviours associated with d4T treatment using ethologically relevant thigmotaxis and burrowing behaviours in adult rats. Detailed neuropathological response was also examined using neurochemistry, electron microscopy, and proteomics. After 2 intravenous injections of d4T (50 mg/kg, 4 days apart), rats developed hind paw mechanical hypersensitivity, which plateaued at 21 days after initial d4T injection, a time that these animals also had significant changes in thigmotaxis and burrowing behaviours when compared to the controls; reductions in hind paw intraepidermal nerve fibre density and CGRP/IB4 immunoreactivity in L5 spinal dorsal horn, suggesting injury to both the peripheral and central terminals of L5 dorsal root ganglion neurons; and increases in myelinated and unmyelinated axon diameters in the sural nerve, suggesting axonal swelling. However, no significant glial and inflammatory cell response to d4T treatment was observed. Sural nerve proteomics at 7 days after initial d4T injection revealed down-regulated proteins associated with mitochondrial function, highlighting distal axons vulnerability to d4T neurotoxicity. In summary, we have reported complex behavioural changes and a distinctive neuropathology in a clinically relevant rat model of d4T-induced sensory neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.
authors: Department of Surgery and Cancer, Imperial College London, UK Wolfson Centre for Age Related Disease, King's College London, UK Division of Cell and Molecular Biology, Imperial College London, UK Nuffield Department of Clinical Neurosciences, University of Oxford, UK Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors: Wenlong
authors: W
authors: Huang
authors: Margarita
authors: M
authors: Calvo
authors: Kersti
authors: K
authors: Karu
authors: Hans R
authors: HR
authors: Olausen
authors: Gabriella
authors: G
authors: Bathgate
authors: Kenji
authors: K
authors: Okuse
authors: David L H
authors: DLH
authors: Bennett
authors: Andrew S C
authors: ASC
authors: Rice
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D037102:Lectins / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D009478:Neuropeptide Y / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000473:pathology; D018119:Stavudine / Q000009:adverse effects*; D013497:Sural Nerve / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D051700:Activating Transcription Factor 3; D019380:Anti-HIV Agents; D037102:Lectins; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D018119:Stavudine; D015740:Calcitonin Gene-Related Peptide