Methadone and the Kidney: Dissecting Gender Differences in Inflammation and Oxidative Stress Responses

Document Type : Original Article

Authors

1 Student Research Committee, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran

2 Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

3 Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

4 Medical Toxicology and Drug Abuse Research Center, (MTDRC), Department of Physiology, School of Medicine, Birjand University of Medical Sciences, Ghaffari Street, Birjand, Iran

5 Department of Pathology, Pathology and Stem Cell Research Center, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran

6 Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran

10.34172/ahj.1625

Abstract

Abstract
Background: This study explored the gender-specific effects of methadone, a synthetic opioid receptor agonist commonly used in opioid addiction treatment, on renal tissue and function. We aimed to elucidate the underlying mechanisms involving inflammatory pathways and redox system activity.
Methods: Forty-two Wistar rats (200-250 g) were allocated into six groups: three males and three females, each comprised of control, and methadone-treated 5 mg/kg and 20 mg/kg. Over eight weeks, animals received either saline or methadone syrup orally. Blood urea nitrogen (BUN) and serum creatinine (sCr) were measured in serum. The inflammatory cytokines and antioxidant enzyme activity were assessed in left kidneys, which were preserved at -80 °C, while histopathological analysis via H&E staining was done on the formalin-fixed right kidneys.
Findings: Methadone administration resulted in renal tissue injury characterized by enhanced glomerular and interstitial inflammation. Notable increases in malondialdehyde (MDA), BUN, sCr, transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and interleukin 17 (IL-17) were observed in methadone-treated groups, indicating impaired renal function associated with oxidative stress and inflammation, with male rats exhibiting more severe alterations. Conversely, methadone treatment elevated glutathione peroxidase (GPx), and catalase (Cat) activities, predominantly in females.
Conclusion: Prolonged methadone therapy exerts a nephrotoxic effect through the activation of oxidative stress and inflammatory pathways, with male rats displaying greater renal pathology and dysfunction, potentially attributed to diminished antioxidant defenses.

Keywords


  1. Crowley R, Kirschner N, Dunn AS, Bornstein SS, Abraham G, Bush JF, et al. Health and public policy to facilitate effective prevention and treatment of substance use disorders involving illicit and prescription drugs: an American College of Physicians position paper. Ann Intern Med. 2017;166(10):733- 6. doi: 10.7326/m16-2953.
  2. Crowley D, Delargy I. A national model of remote care for assessing and providing opioid agonist treatment during the COVID-19 pandemic: a report. Harm Reduct J. 2020;17(1):49. doi: 10.1186/s12954-020-00394-z.
  3. Pro G, Zaller N. Interaction effects in the association between methadone maintenance therapy and experiences of racial discrimination in US healthcare settings. PLoS One. 2020;15(2):e0228755. doi: 10.1371/journal.pone.0228755.
  4. Vijay A, Bazazi AR, Yee I, Kamarulzaman A, Altice FL. Treatment readiness, attitudes toward, and experiences with methadone and buprenorphine maintenance therapy among people who inject drugs in Malaysia. J Subst Abuse Treat. 2015;54:29-36. doi: 10.1016/j.jsat.2015.01.014.
  5. Graziani M, Nisticò R. Gender differences in pharmacokinetics and pharmacodynamics of methadone substitution therapy. Front Pharmacol. 2015;6:122. doi: 10.3389/ fphar.2015.00122.
  6. Azimi MA, Abu Bakar AY. The use of methadon medicine as a drug medicinal therapy in the treatment of drug addict: a pre-emergency examination to three trainers of drug recovery centers. In: Simposium Antar Bangsa Seminar dan Workshop. Lombong: Redwhite Press; 2019. p. 168-76. doi: 10.32698/2159.
  7. Teoh Bing Fei J, Yee A, Habil MH, Danaee M. Effectiveness of methadone maintenance therapy and improvement in quality of life following a decade of implementation. J Subst Abuse Treat. 2016;69:50-6. doi: 10.1016/j.jsat.2016.07.006.
  8. Suljević D, Šiljak A, Fočak M. Different outcomes of methadone maintenance therapy in rehabilitated and relapsed drug addicts: significance of liver and renal biomarkers. Drug Chem Toxicol. 2022;45(1):470-5. doi: 10.1080/01480545.2020.1722157.
  9. Nielsen FE, Cordtz JJ, Rasmussen TB, Christiansen CF. The association between rhabdomyolysis, acute kidney injury, renal replacement therapy, and mortality. Clin Epidemiol. 2020;12:989-95. doi: 10.2147/clep.S254516.
  10. Alinejad S, Ghaemi K, Abdollahi M, Mehrpour O. Nephrotoxicity of methadone: a systematic review. Springerplus. 2016;5(1):2087. doi: 10.1186/s40064-016- 3757-1.
  11. Cusumano AM, Rosa-Diez GJ, Gonzalez-Bedat MC. Latin American Dialysis and Transplant Registry: experience and contributions to end-stage renal disease epidemiology. World J Nephrol. 2016;5(5):389-97. doi: 10.5527/wjn.v5.i5.389.
  12. Hosszu A, Fekete A, Szabo AJ. Sex differences in renal ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2020;319(2):F149-54. doi: 10.1152/ajprenal.00099.2020.
  13. Ghaderi A, Motmaen M, Abdi I, Rasouli-Azad M. Gender differences in substance use patterns and disorders among an Iranian patient sample receiving methadone maintenance treatment. Electron Physician. 2017;9(9):5354-62. doi: 10.19082/5354.
  14. Amraei M, Mohamadpour M, Hafezi Ahmadi MR, Azizi M, Daemi A, Omidi M, et al. Histopathological study of liver tissue due to methadone consumption and its effect on liver enzymes and inflammatory indices in rat. Drug Des Devel Ther. 2018;12:3785-95. doi: 10.2147/dddt.S182032.
  15. Tahergorabi Z, Rahmani H, Williams J, Moodi M. The effect of methadone on blood glucose, lipids and glucose-modulating hormones in methadone-dependent Wistar rats. Toxicol Res. 2020;36(3):221-6. doi: 10.1007/s43188-019-00019-z .
  16. Pierce TL, Hope W, Raper C. The induction and quantitation of methadone dependence in the rat. J Pharmacol Toxicol Methods. 1996;36(3):137-46. doi: 10.1016/s1056- 8719(96)00108-6.
  17. Shakeri SH, Hassanian-Moghaddam H, Zamani N. Safety of naloxone in opioid-naïve methadone intoxicated patients; a case series study. Arch Acad Emerg Med. 2020;8(1):e16.
  18. Zeynali F, Nematbakhsh M, Mojtahedi H, Poorshahnazari A, Talebi A, Pezeshki Z, et al. Protective role of aerobic exercise against cisplatin-induced nephrotoxicity in rats. Asian J Sports Med. 2015;6(3):e24901. doi: 10.5812/asjsm.24901.
  19. Jamshidi HR, Kalantar H. Effect of sodium selenide on renal toxicity induced by mercuric chloride in rat. Int J Med Lab. 2020;7(2):90-101. doi: 10.18502/ijml.v7i2.2912.
  20. Faridi S, Delirezh N, Abtahi Froushani SM. Beneficial effects of hydroalcoholic extract of saffron in alleviating experimental autoimmune diabetes in C57bl/6 mice. Iran J Allergy Asthma Immunol. 2019;18(1):38-47.
  21. Hosseinian S, Khajavi Rad A, Ebrahimzadeh Bideskan A, Soukhtanloo M, Sadeghnia H, Shafei MN, et al. Thymoquinone ameliorates renal damage in unilateral ureteral obstruction in rats. Pharmacol Rep. 2017;69(4):648-57. doi: 10.1016/j. pharep.2017.03.002.
  22. Bejeshk MA, Beik A, Aminizadeh AH, Salimi F, Bagheri F, Sahebazzamani M, et al. Perillyl alcohol (PA) mitigates inflammatory, oxidative, and histopathological consequences of allergic asthma in rats. Naunyn Schmiedebergs Arch Pharmacol. 2023;396(6):1235-45. doi: 10.1007/s00210-023- 02398-5.
  23. Degenhardt L, Charlson F, Mathers B, Hall WD, Flaxman AD, Johns N, et al. The global epidemiology and burden of opioid dependence: results from the global burden of disease 2010 study. Addiction. 2014;109(8):1320-33. doi: 10.1111/ add.12551.
  24. Khazaee-Pool M, Moeeni M, Ponnet K, Fallahi A, Jahangiri L, Pashaei T. Perceived barriers to methadone maintenance treatment among Iranian opioid users. Int J Equity Health. 2018;17(1):75. doi: 10.1186/s12939-018-0787-z.
  25. Fraser DW. Methadone overdose. Illicit use of pharmaceutically prepared parenteral narcotics. JAMA. 1971;217(10):1387-9. doi: 10.1001/jama.1971.03190100069019.
  26. AlBasher G, Alfarraj S, Alarifi S, Alkhtani S, Almeer R, Alsultan N, et al. Nephroprotective role of selenium nanoparticles against glycerol-induced acute kidney injury in rats. Biol Trace Elem Res. 2020;194(2):444-54. doi: 10.1007/s12011- 019-01793-5 .
  27. Ling GS, Tappe NS, Inturrisi CE. Methadone induced physical dependence in the rat. Life Sci. 1984;34(7):683-90. doi: 10.1016/0024-3205(84)90233-9.
  28. Fenn JM, Laurent JS, Sigmon SC. Increases in body mass index following initiation of methadone treatment. J Subst Abuse Treat. 2015;51:59-63. doi: 10.1016/j.jsat.2014.10.007.
  29. Motamedi F, Nematbakhsh M, Monajemi R, Pezeshki Z, Talebi A, Zolfaghari B, et al. Effect of pomegranate flower extract on cisplatin-induced nephrotoxicity in rats. J Nephropathol. 2014;3(4):133-8. doi: 10.12860/jnp.2014.26.
  30. Song SJ, Kim SM, Lee SH, Moon JY, Hwang HS, Kim JS, et al. Rhabdomyolysis-induced AKI was ameliorated in NLRP3 KO mice via alleviation of mitochondrial lipid peroxidation in renal tubular cells. Int J Mol Sci. 2020;21(22):8564. doi: 10.3390/ijms21228564.
  31. Chan YY, Yang SN, Lin JC, Chang JL, Lin JG, Lo WY. Inflammatory response in heroin addicts undergoing methadone maintenance treatment. Psychiatry Res. 2015;226(1):230-4. doi: 10.1016/j.psychres.2014.12.053.
  32. Katz Y, Nadiv O, Beer Y. Interleukin-17 enhances tumor necrosis factor alpha-induced synthesis of interleukins 1,6, and 8 in skin and synovial fibroblasts: a possible role as a “fine-tuning cytokine” in inflammation processes. Arthritis Rheum. 2001;44(9):2176-84. doi: 10.1002/1529- 0131(200109)44:9 < 2176::aid-art371 > 3.0.co;2-4.
  33. Barbosa J, Faria J, Garcez F, Leal S, Afonso LP, Nascimento AV, et al. Repeated administration of clinical doses of tramadol and tapentadol causes hepato- and nephrotoxic effects in Wistar rats. Pharmaceuticals (Basel). 2020;13(7):149. doi: 10.3390/ph13070149.
  34. Chen Y, Ji LL, Liu TY, Wang ZT. Evaluation of gender-related differences in various oxidative stress enzymes in mice. Chin J Physiol. 2011;54(6):385-90. doi: 10.4077/cjp.2011.Amm080.
  35. Liang Q, Sheng Y, Jiang P, Ji L, Xia Y, Min Y, et al. The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury. Toxicology. 2011;280(1-2):61-9. doi: 10.1016/j.tox.2010.11.010.
  36. Lima-Posada I, Portas-Cortés C, Pérez-Villalva R, Fontana F, Rodríguez-Romo R, Prieto R, et al. Gender differences in the acute kidney injury to chronic kidney disease transition. Sci Rep. 2017;7(1):12270. doi: 10.1038/s41598-017-09630-2.
  37. Rosenkrantz H, Fleischman RW. In vivo carcinogenesis assay of DL-methadone.HCl in rodents. Fundam Appl Toxicol. 1988;11(4):640-51. doi: 10.1016/0272-0590(88)90127-3.