Abstract
HIV-associated sensory neuropathy (HIV-SN) is the most frequent manifestation of HIV disease. It often presents with significant neuropathic pain and is associated with previous exposure to neurotoxic nucleoside reverse transcriptase inhibitors. However, HIV-SN prevalence remains high even in resource-rich settings where these drugs are no longer used. Previous evidence suggests that exposure to indinavir, a protease inhibitor commonly used in antiretroviral therapy, may link to elevated HIV-SN risk. Here we investigated whether indinavir treatment was associated with the development of a "dying back" axonal neuropathy and changes in pain-relevant limb withdrawal and thigmotactic behaviours. Following two intravenous injections of indinavir (50 mg/kg, 4 days apart), adult rats developed hindpaw mechanical hypersensitivity, which peaked around 2 weeks post first injection (44% reduction from baseline). At this time, animals also had 1) significantly changed thigmotactic behaviour (62% reduction in central zone entries) comparing to the controls and 2) a significant reduction (45%) in hindpaw intraepidermal nerve fibre density. Treatment with gabapentin, but not amitriptyline, was associated with a complete attenuation of hindpaw mechanical hypersensitivity observed with indinavir treatment. Furthermore, we found a small but significant increase in microglia with the effector morphology in the lumbar spinal dorsal horn in indinavir-treated animals, coupled with significantly increased expression of phospho-p38 in microglia. In summary, we have reported neuropathic pain-related sensory and behavioural changes accompanied by a significant loss of hindpaw skin sensory innervation in a rat model of indinavir-induced peripheral neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.
(C) 2016 International Association for the Study of Pain
(C) 2016 International Association for the Study of Pain
| Original language | English |
|---|---|
| Pages (from-to) | 75-85 |
| Number of pages | 11 |
| Journal | Pain |
| Volume | 158 |
| Issue number | 1 |
| Early online date | 23 Sept 2016 |
| DOIs | |
| Publication status | Published - Jan 2017 |
Bibliographical note
The research leading to these results is part of the EUROPAIN Collaboration, which has received support from the Innovative Medicines Initiative Joint Undertaking, under grant agreement no 115007, resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007‐2013) and EFPIA companies’ in kind contribution.We thank Pfizer for providing indinavir and gabapentin. MC received Conicyt grant (Folio 82130016),to complete this work.
Keywords
- HIV
- peripheral
- neuropathy
- neuropathic pain
- rat
- indinavir
- thigmotaxis
Access to Document
- PAIN-D-14-13965_R2
NOTICE: this is the author’s version of a work that was accepted for publication in PAIN. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in journal Pain 158(1) DOI: 10.1097/j.pain.0000000000000727.
