, Volume 27, Issue 2, pp 387–396 | Cite as

Establishment and characterisation of a stavudine (d4T)-induced rat model of antiretroviral toxic neuropathy (ATN) using behavioural and pharmacological methods

  • Andy Kuo
  • Janet R. Nicholson
  • Laura Corradini
  • Maree T. SmithEmail author
Original Article


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.


Amitriptyline 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.

Author contributions

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.

Supplementary material

10787_2018_551_MOESM1_ESM.docx (274 kb)
Supplementary material 1 (DOCX 274 kb)


  1. Aouizerat BE et al (2010) Risk factors and symptoms associated with pain in HIV-infected adults. J Assoc Nurses AIDS Care JANAC 21:125–133. CrossRefGoogle Scholar
  2. Bruce RD et al (2017a) 2017 HIV medicine association of infectious diseases society of America clinical practice guideline for the management of chronic pain in patients living with human immunodeficiency virus. Clin Infect Dis 65:1601–1606. CrossRefGoogle Scholar
  3. Bruce RD et al (2017b) 2017 HIVMA of IDSA clinical practice guideline for the management of chronic pain in patients living with HIV. Clin Infect Dis 65:e1–e37. CrossRefGoogle Scholar
  4. Burdo TH, Miller AD (2014) Animal models of HIV peripheral neuropathy. Future Virol 9:465–474. CrossRefGoogle Scholar
  5. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63CrossRefGoogle Scholar
  6. Cunningham CO (2018) Opioids and HIV infection: from pain management to addiction treatment. Top Antivir Med 25:143–146Google Scholar
  7. DeLeo JA (2006) Basic science of pain. J Bone Jt Surg 88(Suppl 2):58–62Google Scholar
  8. Dorsey SG, Leitch CC, Renn CL, Lessans S, Smith BA, Wang XM, Dionne RA (2009) Genome-wide screen identifies drug-induced regulation of the gene giant axonal neuropathy (Gan) in a mouse model of antiretroviral-induced painful peripheral neuropathy. Biol Res Nurs 11:7–16. CrossRefGoogle Scholar
  9. Dworkin RH et al (2010) Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 85:S3–14. CrossRefGoogle Scholar
  10. Ferrari S, Vento S, Monaco S, Cavallaro T, Cainelli F, Rizzuto N, Temesgen Z (2006) Human immunodeficiency virus-associated peripheral neuropathies. Mayo Clin Proc 81:213–219. CrossRefGoogle Scholar
  11. Finnerup NB et al (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14:162–173. CrossRefGoogle Scholar
  12. Haggerty GC (1991) Strategy for and experience with neurotoxicity testing of new pharmaceuticals. J Am Coll Toxicol 10:677–688. CrossRefGoogle Scholar
  13. Hill A et al (2007) Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Expert Opin Pharmacother 8:679–688. CrossRefGoogle Scholar
  14. Huang W et al (2013) A clinically relevant rodent model of the HIV antiretroviral drug stavudine induced painful peripheral neuropathy. Pain 154:560–575. CrossRefGoogle Scholar
  15. Joseph EK, Chen X, Khasar SG, Levine JD (2004) Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat. Pain 107:147–158CrossRefGoogle Scholar
  16. Kamerman PR, Moss PJ, Weber J, Wallace VC, Rice AS, Huang W (2012) Pathogenesis of HIV-associated sensory neuropathy: evidence from in vivo and in vitro experimental models. J Peripher Nerv Syst 17:19–31. CrossRefGoogle Scholar
  17. Kieburtz KD, Seidlin M, Lambert JS, Dolin R, Reichman R, Valentine F (1992) Extended follow-up of peripheral neuropathy in patients with AIDS and AIDS-related complex treated with dideoxyinosine. J Acquir Immune Defic Syndr 5:60–64Google Scholar
  18. Kuo A, Smith MT (2018) In vivo profiling of four centrally administered opioids for antinociception, constipation and respiratory depression: between-colony differences in Sprague Dawley rats. Clin Exp Pharmacol Physiol. Google Scholar
  19. Liu B, Liu X, Tang SJ (2016) Interactions of opioids and HIV infection in the pathogenesis of chronic pain. Front Microbiol 7:103. Google Scholar
  20. Mello A, Gravel T (2017) HIV pain management challenges and alternative therapies. Nursing 47:67–70. CrossRefGoogle Scholar
  21. Moore RA, Chi CC, Wiffen PJ, Derry S, Rice AS (2015a) Oral nonsteroidal anti-inflammatory drugs for neuropathic pain. Cochrane Database Syst Rev. Google Scholar
  22. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ (2015b) Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. Google Scholar
  23. Moser VC, MacPhail RC (1990) Comparative sensitivity of neurobehavioral tests for chemical screening. Neurotoxicology 11:335–344Google Scholar
  24. Nasirinezhad F, Jergova S, Pearson JP, Sagen J (2015) Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy. Neuropharmacology 95:100–109. CrossRefGoogle Scholar
  25. Ngassa Mbenda HG, Wadley A, Lombard Z, Cherry C, Price P, Kamerman P (2017) Genetics of HIV-associated sensory neuropathy and related pain in Africans. J Neurovirol 23:511–519. CrossRefGoogle Scholar
  26. NHMRC (2013) Australian code for the care and use of animals for scientific purposes, 8th edn. Australian Government, CanberraGoogle Scholar
  27. Nicholas PK, Corless IB, Evans LA (2014) Peripheral neuropathy in HIV: an analysis of evidence-based approaches. J Assoc Nurses AIDS Care 25:318–329. CrossRefGoogle Scholar
  28. Phillips TJ et al (2014) Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: a cross-sectional deep profiling study. Pain 155:1846–1860. CrossRefGoogle Scholar
  29. Pillay P, Wadley AL, Cherry CL, Karstaedt AS, Kamerman PR (2015) Pharmacological treatment of painful HIV-associated sensory neuropathy. S Afr Med J 105:769–772. CrossRefGoogle Scholar
  30. Schutz SG, Robinson-Papp J (2013) HIV-related neuropathy: current perspectives. HIV AIDS (Auckl) 5:243–251. Google Scholar
  31. Serdyuk SE, Gmiro VE (2015) Mesaton (phenylephrine) potentiates the antidepressant and eliminates the sedative action of amitriptyline in rats. Neurosci Behav Physiol 45:760–764. CrossRefGoogle Scholar
  32. Shenoy P, Kuo A, Vetter I, Smith MT (2017) Optimization and in vivo profiling of a refined rat model of walker 256 breast cancer cell-induced bone pain using behavioral, radiological, histological, immunohistochemical and pharmacological methods. Front Pharmacol 8:442. CrossRefGoogle Scholar
  33. Singer EJ, Valdes-Sueiras M, Commins D, Levine A (2010) Neurologic presentations of AIDS. Neurol Clin 28:253–275. CrossRefGoogle Scholar
  34. Staff NP, Grisold A, Grisold W, Windebank AJ (2017) Chemotherapy-induced peripheral neuropathy: a current review. Ann Neurol 81:772–781. CrossRefGoogle Scholar
  35. Verma S, Estanislao L, Simpson D (2005) HIV-associated neuropathic pain: epidemiology, pathophysiology and management. CNS Drugs 19:325–334CrossRefGoogle Scholar
  36. Walker-Bone K, Doherty E, Sanyal K, Churchill D (2017) Assessment and management of musculoskeletal disorders among patients living with HIV. Rheumatology (Oxford) 56:1648–1661. CrossRefGoogle Scholar
  37. Wallace VC et al (2007) Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy. Pain 133:47–63. CrossRefGoogle Scholar
  38. Weber J, Mitchell D, Kamerman PR (2007) Oral administration of stavudine induces hyperalgesia without affecting activity in rats. Physiol Behav 92:807–813. CrossRefGoogle Scholar
  39. WHO (2013) Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. In: Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. WHO Guidelines Approved by the Guidelines Review Committee, GenevaGoogle Scholar
  40. WHO (2018) WHO Global Health Observatory data—HIV/AIDS. WHO. Accessed 23 Aug 2018
  41. Wiffen PJ, Derry S, Bell RF, Rice AS, Tolle TR, Phillips T, Moore RA (2017) Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev 6:CD007938. Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Centre for Integrated Preclinical Drug Development, School of Biomedical Sciences, Faculty of MedicineThe University of QueenslandBrisbaneAustralia
  2. 2.Boehringer Ingelheim Pharma GmbH & Co. KGBiberachGermany
  3. 3.School of Pharmacy, Faculty of Health and Behavioural SciencesThe University of QueenslandBrisbaneAustralia

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