1. A rodent model of HIV protease inhibitor indinavir induced peripheral neuropathy
- Author
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David L.H. Bennett, Andrew S.C. Rice, Margarita Calvo, Wenlong Huang, Tim Pheby, and Astellas Pharma Europe B.V
- Subjects
Male ,0301 basic medicine ,Pathology ,INFLAMMATORY PAIN ,Cyclohexanecarboxylic Acids ,HIV Infections ,Indinavir ,Pharmacology ,Neuropathic pain ,Peripheral ,0302 clinical medicine ,Anesthesiology ,Ganglia, Spinal ,RAT MODEL ,ANXIETY ,Amitriptyline ,Amines ,gamma-Aminobutyric Acid ,HYPERSENSITIVITY ,Pain Measurement ,Analgesics ,medicine.diagnostic_test ,NERVE-FIBER DENSITY ,Microfilament Proteins ,11 Medical And Health Sciences ,Pathophysiology ,PAINFUL NEUROPATHY ,Spinal Cord ,Neurology ,Hyperalgesia ,Microglia ,Gabapentin ,Metacarpus ,Life Sciences & Biomedicine ,BEHAVIOR ,medicine.drug ,Pain Threshold ,medicine.medical_specialty ,Calcitonin Gene-Related Peptide ,Clinical Neurology ,Statistics, Nonparametric ,17 Psychology And Cognitive Sciences ,03 medical and health sciences ,Physical Stimulation ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Rats, Wistar ,Thigmotaxis ,Science & Technology ,business.industry ,Calcium-Binding Proteins ,Neurosciences ,HIV ,HIV Protease Inhibitors ,medicine.disease ,Rats ,Neuropathy ,Disease Models, Animal ,030104 developmental biology ,Anesthesiology and Pain Medicine ,Peripheral neuropathy ,SENSORY NEUROPATHY ,Gene Expression Regulation ,Skin biopsy ,Exploratory Behavior ,RISK-FACTORS ,Neuralgia ,Rat ,SKIN BIOPSY ,Neurology (clinical) ,Neurosciences & Neurology ,business ,030217 neurology & neurosurgery - 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. 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. more...
- Published
- 2016