A rodent model of HIV protease inhibitor indinavir induced peripheral neuropathy

Wenlong Huang, Margarita Calvo, Tim Pheby, David LH Bennett, Andrew S C Rice

Research output: Contribution to journalArticle

4 Citations (Scopus)
8 Downloads (Pure)

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
Original languageEnglish
Pages (from-to)75-85
Number of pages11
JournalPain
Volume158
Issue number1
Early online date23 Sep 2016
DOIs
Publication statusPublished - Jan 2017

Keywords

  • HIV
  • peripheral
  • neuropathy
  • neuropathic pain
  • rat
  • indinavir
  • thigmotaxis

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