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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.

Type

Journal article

Journal

Pain

Publication Date

23/09/2016

Addresses

1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, UK 2Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile 3. Pain Research, Department of Surgery & Cancer, Imperial College London, UK 4. Nuffield Department of Clinical Neurosciences, University of Oxford, UK 5Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK *=Joint first authors.