A clinically relevant rodent model of the HIV antiretroviral drug stavudine induced painful peripheral neuropathy
- 1 April 2013
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Pain
- Vol. 154 (4), 560-575
- https://doi.org/10.1016/j.pain.2012.12.023
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 analgesicsKeywords
This publication has 81 references indexed in Scilit:
- The response of spinal microglia to chemotherapy-evoked painful peripheral neuropathies is distinct from that evoked by traumatic nerve injuriesNeuroscience, 2011
- Comparison of dorsal root ganglion gene expression in rat models of traumatic and HIV‐associated neuropathic painEuropean journal of pain, 2009
- Anxiety-like behaviour is attenuated by gabapentin, morphine and diazepam in a rodent model of HIV anti-retroviral-associated neuropathic painNeuroscience Letters, 2008
- Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathyPain, 2007
- Axonal and periaxonal swelling precede peripheral neurodegeneration in KCC3 knockout miceNeurobiology of Disease, 2007
- Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic painBrain, 2007
- The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L‐29) on pain behaviour in rodent models of neuropathyBritish Journal of Pharmacology, 2007
- Further characterization of a rat model of varicella zoster virus–associated pain: Relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugsNeuroscience, 2007
- Peripheral neuropathic pain—a multidimensional burden for patientsEuropean journal of pain, 2001
- Ethical guidelines for investigations of experimental pain in conscious animalsPain, 1983