Establishment and characterisation of a stavudine (d4T)-induced rat model of antiretroviral toxic neuropathy (ATN) using behavioural and pharmacological methods
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Human immuno-deficiency virus (HIV) associated sensory neuropathy (SN) is a frequent complication of HIV infection. It is extremely difficult to alleviate and hence the quality of life of affected individuals is severely and adversely impacted. Stavudine (d4T) is an antiretroviral drug that was widely used globally prior to 2010 and that is still used today in resource-limited settings. Its low cost and relatively good efficacy when included in antiretroviral dosing regimens means that there is a large population of patients with d4T-induced antiretroviral toxic neuropathy (ATN). As there are no FDA approved drugs for alleviating ATN, it is important to establish rodent models to probe the pathobiology and to identify potentially efficacious new drug treatments. In the model establishment phase, d4T administered intravenously at a cumulative dose of 375 mg/kg in male Wistar Han rats evoked temporal development of sustained mechanical allodynia in the hindpaws from day 10 to day 30 after initiation of d4T treatment. As this d4T dosing regimen was also well tolerated, it was used for ATN model induction for subsequent pharmacological profiling. Both gabapentin at 30–100 mg/kg and morphine at 0.3–2 mg/kg given subcutaneously produced dose-dependent relief of mechanical allodynia with estimated ED50’s of 19 mg/kg and 0.4 mg/kg, respectively. In contrast, intraperitoneal administration of meloxicam or amitriptyline up to 30 mg/kg and 7 mg/kg, respectively, lacked efficacy. Our rat model of ATN is suitable for investigation of the pathophysiology of d4T-induced SN as well as for profiling novel molecules from analgesic drug discovery programs.
KeywordsAmitriptyline Gabapentin HIV Morphine Meloxicam Stavudine
AK and this project were supported financially by funds from an Australian Research Council (ARC) Large Linkage Grant [LP120200623] in collaboration with Boehringer Ingelheim Pharma GmbH & Co. KG. JN and LC are paid employees of Boehringer Ingelheim Pharma GmbH & Co. KG. The authors acknowledge the Queensland Government Smart State Research Facilities Programme for supporting CIPDD research infrastructure. CIPDD is also supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. The authors thank Dr. Steve Edwards, Ms. Jacintha Lourdesamy, Ms. Kelly Sweeney, Mr. Michael Osborne, Ms. Angela Raboczyj and Ms. Ashleigh Hicks from the Centre for Integrated Preclinical Drug Development at The University of Queensland, for their technical assistance.
AK contributed to the research design, performance of the experiments, data analysis and drafted the manuscript. The study was conceived and supervised by JN, LC and MS. All authors edited, read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors have no relevant conflicts of interest to declare in association with this work.
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