A rodent model of HIV protease inhibitor indinavir induced peripheral neuropathy.
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. After 2 intravenous injections of indinavir (50 mg/kg, 4 days apart), adult rats developed hind paw 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 with the controls and (2) a significant reduction (45%) in hind paw intraepidermal nerve fibre density. Treatment with gabapentin, but not amitriptyline, was associated with a complete attenuation of hind paw 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 hind paw 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.
School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.|Pain Research, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
Wenlong
W
Huang
Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Margarita
M
Calvo
Pain Research, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
Tim
T
Pheby
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
David L H
DLH
Bennett
Pain Research, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.|Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom.
Andrew S C
ASC
Rice
D000588:Amines / Q000627:therapeutic use; D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D000077206:Gabapentin; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015658:HIV Infections / Q000139:chemically induced* / Q000150:complications*; D017320:HIV Protease Inhibitors / Q000633:toxicity*; D006930:Hyperalgesia / Q000209:etiology; D019469:Indinavir / Q000633:toxicity*; D008297:Male; D008663:Metacarpus / Q000187:drug effects / Q000294:innervation; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010812:Physical Stimulation / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018709:Statistics, Nonparametric; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use
C100745:Aif1 protein, rat; D000588:Amines; D000700:Analgesics; D002135:Calcium-Binding Proteins; D003509:Cyclohexanecarboxylic Acids; D005904:Glial Fibrillary Acidic Protein; D017320:HIV Protease Inhibitors; D008840:Microfilament Proteins; D005680:gamma-Aminobutyric Acid; D019469:Indinavir; D000077206:Gabapentin; D015740:Calcitonin Gene-Related Peptide
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