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

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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

Fingerprint

Indinavir
HIV Protease Inhibitors
Peripheral Nervous System Diseases
Rodentia
HIV
Microglia
Neuralgia
Hypersensitivity
Pain
Amitriptyline
Reverse Transcriptase Inhibitors
Therapeutics
Protease Inhibitors
Nerve Fibers
Nucleosides
Intravenous Injections
Analgesics
Extremities
Skin
Injections

Keywords

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

Cite this

A rodent model of HIV protease inhibitor indinavir induced peripheral neuropathy. / Huang, Wenlong; Calvo, Margarita; Pheby, Tim; Bennett, David LH ; Rice, Andrew S C.

In: Pain, Vol. 158, No. 1, 01.2017, p. 75-85.

Research output: Contribution to journalArticle

Huang, Wenlong ; Calvo, Margarita ; Pheby, Tim ; Bennett, David LH ; Rice, Andrew S C. / A rodent model of HIV protease inhibitor indinavir induced peripheral neuropathy. In: Pain. 2017 ; Vol. 158, No. 1. pp. 75-85.
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AB - 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

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