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Neurotoxic, Hepatotoxic and Nephrotoxic Effects of Tramadol Administration in Rats

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Abstract

The current study was performed to study the tramadol HCL toxic effects on the brain, liver, and kidney of adult male rats. Forty male adult albino rats were divided into 4 groups; the first one was considered as a control group, the others were orally administrated with 25, 50, and 100 b.wt. representing therapeutic, double therapeutic, and 4 times therapeutic doses, respectively, of tramadol HCL daily for 1 month. Serum and brain, hepatic, and renal tissues were collected for biochemical and molecular investigations. Tramadol HCL resulted in a significant increase in the brain serotonin, 8-hydroxy-2′-deoxyguanosine (8-OHdG), and malonyldialdehyde (MDA) levels with a significant decrease in the reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. At the same line, hepatic and renal 8-OHdG and MDA levels showed a significant increase with a significant decrease in reduced glutathione (GSH), CAT, and SOD activities. In addition, hepatic and renal function parameters including serum alanine amino transferase (ALT), aspartate amino transferase (AST), urea, and creatinine were increased in a dose-dependent manner. At the molecular levels, hepatic cytochrome P5402E1 (CYP2E1), renal Kidney Injury Molecule-1 (KIM-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) showed also a significant increase in the expression levels. Histopathological evaluation of the brain confirmed the above biochemical results. In conclusion, tramadol HCL induced neurotoxic, hepatotoxic, and nephrotoxic effects in a manner relative to its concentration by affecting brain serotonin levels and hepatic and renal function, with the production of DNA damage and oxidative stress.

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References

  • Abdel-Zaher AO, Abdel-Rahman MS, Elwasei FM (2011) Protective effect of Nigella sativa oil against tramadol-induced tolerance and dependence in mice: role of nitric oxide and oxidative stress. Neurotoxicology 32:725–733

    Article  CAS  PubMed  Google Scholar 

  • Adikwu E, Bokolo B (2017) Prospects of N-acetylcysteine and melatonin as treatments for tramadol-induced renal toxicity in albino rats. Pharm Sci 23:172–181

    Article  Google Scholar 

  • Bameri B, Shaki F, Ahangar N, Ataee R, Samadi M, Mohammadi H (2018) Evidence for the involvement of the dopaminergic system in seizure and oxidative damage induced by tramadol. Int J Toxicol 37:164–170

    Article  CAS  PubMed  Google Scholar 

  • Bamigbade TA, Davidson C, Langford RM, Stamford JA (1997) Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 79:352–356

    Article  CAS  PubMed  Google Scholar 

  • Bancroft JD, Gamble M (2008) Theory and practice of histological techniques. 6th Edition, Churchill Livingstone, Elsevier, China

  • Barbosa J, Faria J, Queirós O, Moreira R, Carvalho F, Dinis-Oliveira RJ (2016) Comparative metabolism of tramadol and tapentadol: a toxicological perspective. Drug Metab Rev 48:577–592

    Article  CAS  PubMed  Google Scholar 

  • Barbosa J, Faria J, Leal S, Afonso LP, Lobo J, Queiros O, Moreira R, Carvalho F, Dinis-Oliveira RJ (2017) Acute administration of tramadol and tapentadol at effective analgesic and maximum tolerated doses causes hepato- and nephrotoxic effects in Wistar rats. Toxicology 389:118–129

    Article  CAS  PubMed  Google Scholar 

  • Bloms-Funke P, Dremencov E, Cremers TI, Tzschentke TM (2011) Tramadol increases extracellular levels of serotonin and noradrenaline as measured by in vivo microdialysis in the ventral hippocampus of freely-moving rats. Neurosci Lett 490:191–195

    Article  CAS  PubMed  Google Scholar 

  • Butterfield DA, Castegna A, Lauderback CM, Drake J (2002) Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol Aging 23:655–664

    Article  PubMed  Google Scholar 

  • Costa I, Oliveira A, Guedes de Pinho P, Teixeira HM, Moreira R, Carvalho F, Jorge Dinis-Oliveira R (2013) Postmortem redistribution of tramadol and o-desmethyltramadol. J Anal Toxicol 37:670–675

    Article  CAS  PubMed  Google Scholar 

  • DePriest AZ, Puet BL, Holt AC, Roberts A, Cone EJ (2015) Metabolism and disposition of prescription opioids: a review. Forensic Sci Rev 27:115–145

    CAS  PubMed  Google Scholar 

  • Driessen B, Reimann W (1992) Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol 105:147–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dugbartey GJ, Peppone LJ, de Graaf IAM (2016) An integrative view of cisplatin-induced renal and cardiac toxicities: molecular mechanisms, current treatment challenges and potential protective measures. Toxicology 371:58–66

    Article  CAS  PubMed  Google Scholar 

  • Elkhateeb A, El Khishin I, Megahed O, Mazen F (2015) Effect of Nigella sativa Linn oil on tramadol-induced hepato- and nephrotoxicity in adult male albino rats. Toxicol Rep 2:512–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faria J, Barbosa J, Leal S, Afonso LP, Lobo J, Moreira R, Queiros O, Carvalho F, Dinis-Oliveira RJ (2017) Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats. Toxicology 385:38–47

    Article  CAS  PubMed  Google Scholar 

  • Fawzi MM (2011) Some medicolegal aspects concerning tramadol abuse: the new Middle East youth plague 2010. An Egyptian overview. Egypt J Forensic Sci 1:99–102

    Article  Google Scholar 

  • Gillman PK (2005) Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 95:434–441

    Article  CAS  PubMed  Google Scholar 

  • Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43:879–923

    Article  CAS  PubMed  Google Scholar 

  • Guo L, Takino T, Endo Y, Domoto T, Sato H (2012) Shedding of kidney injury molecule-1 by membrane-type 1 matrix metalloproteinase. J Biochem 152:425–432

    Article  CAS  PubMed  Google Scholar 

  • Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV (2002) Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 62:237–244

    Article  CAS  PubMed  Google Scholar 

  • Hussein MA, Haytham AA, Mona MA (2015) Ameliorative effects of phycocyanin against gibberellic acid induced hepatotoxicity. Pestic Biochem Physiol 119:28–32

    Article  CAS  PubMed  Google Scholar 

  • Jin SE, Ha H, Seo CS, Shin HK, Jeong SJ (2016) Expression of cytochrome P450s in the liver of rats administered with Socheongryong-tang, a traditional herbal formula. Pharmacogn Mag 12:211–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kessova I, Cederbaum AI (2003) CYP2E1: biochemistry, toxicology, regulation and function in ethanol-induced liver injury. Curr Mol Med 3:509–518

    Article  CAS  PubMed  Google Scholar 

  • Lagard C, Chevillard L, Malissin I, Risede P, Callebert J, Labat L, Launay JM, Laplanche JL, Megarbane B (2016) Mechanisms of tramadol-related neurotoxicity in the rat: does diazepam/tramadol combination play a worsening role in overdose? Toxicol Appl Pharmacol 310:108–119

    Article  CAS  PubMed  Google Scholar 

  • Lenz O, Elliot SJ, Stetler-Stevenson WG (2000) Matrix metalloproteinases in renal development and disease. J Am Soc Nephrol 11:574–581

    Article  CAS  PubMed  Google Scholar 

  • Liu LW, Lu J, Wang XH, Fu SK, Li Q, Lin FQ (2013) Neuronal apoptosis in morphine addiction and its molecular mechanism. Int J Clin Exp Med 6:540–545

    PubMed  PubMed Central  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R (2017) Trends in tramadol: pharmacology, metabolism, and misuse. Anesth Analg 124:44–51

    Article  CAS  PubMed  Google Scholar 

  • Mohamed HM, Mahmoud AM (2019) Chronic exposure to the opioid tramadol induces oxidative damage, inflammation and apoptosis, and alters cerebral monoamine neurotransmitters in rats. Biomed Pharmacother 110:239–247

    Article  CAS  PubMed  Google Scholar 

  • Mohamed TM, Ghaffar HMA, El Husseiny RMR (2013) Effects of tramadol, clonazepam, and their combination on brain mitochondrial complexes. Toxicol Ind Health 31:1325–1333

    Article  PubMed  CAS  Google Scholar 

  • Mohamed TM, Ghaffar HM, El Husseiny RM (2015) Effects of tramadol, clonazepam, and their combination on brain mitochondrial complexes. Toxicol Ind Health 31:1325–1333

    Article  CAS  PubMed  Google Scholar 

  • Musial K, Zwolinska D (2011) Matrix metalloproteinases (MMP-2, 9) and their tissue inhibitors (TIMP-1, 2) as novel markers of stress response and atherogenesis in children with chronic kidney disease (CKD) on conservative treatment. Cell Stress Chaperones 16:97–103

    Article  CAS  PubMed  Google Scholar 

  • Nair V, Turner GA (1984) The thiobarbituric acid test for lipid peroxidation: structure of the adduct with malondialdehyde. Lipids 19:84–85

    Article  Google Scholar 

  • Noori S, Mahboob T (2010) Antioxidant effect of carnosine pretreatment on cisplatin-induced renal oxidative stress in rats. Indian J Clin Biochem 25:86–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pinho S, Oliveira A, Costa I, Gouveia CA, Carvalho F, Moreira RF, Dinis-Oliveira RJ (2013) Simultaneous quantification of tramadol and O-desmethyltramadol in hair samples by gas chromatography–electron impact/mass spectrometry. Biomed Chromatogr 27:1003–1011

    Article  CAS  PubMed  Google Scholar 

  • Ragab IK, Mohamed HZE (2017) Histological changes of the adult albino rats entorhinal cortex under the effect of tramadol administration: histological and morphometric study. Alexandria J Med 53:123–133

    Article  Google Scholar 

  • Rahman I, Kode A, Biswas S (2006) Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc 1:3159–3165

    Article  CAS  PubMed  Google Scholar 

  • Saber TM, Elgaml SA, Ali HA, Saleh AA (2015) Protective effect of Spirulina platensis against aluminium-induced nephrotoxicity and DNA damage in rats. Toxicol Environ Chem 97:8, 1113–1123. https://doi.org/10.1080/02772248.2015.1091890

  • Salahshoor MR, Khashiadeh M, Roshankhah S, Kakabaraei S, Jalili C (2016) Protective effect of crocin on liver toxicity induced by morphine. Res Pharm Sci 11:120–129

    PubMed  PubMed Central  Google Scholar 

  • Sharma AK, Mauer SM, Kim Y, Michael AF (1995) Altered expression of matrix metalloproteinase-2, TIMP, and TIMP-2 in obstructive nephropathy. J Lab Clin Med 125:754–761

    CAS  PubMed  Google Scholar 

  • Sheweita SA (2000) Drug-metabolizing enzymes: mechanisms and functions. Curr Drug Metab 1:107–132

    Article  CAS  PubMed  Google Scholar 

  • Sheweita SA, Almasmari AA, El-Banna SG (2018) Tramadol-induced hepato- and nephrotoxicity in rats: role of curcumin and gallic acid as antioxidants. PLoS One 13:e0202110

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Takeshita J, Litzinger MH (2009) Serotonin syndrome associated with tramadol. Prim Care Companion J Clin Psychiatry 11(5):273

    Article  PubMed  PubMed Central  Google Scholar 

  • Thukral SK, Nordone PJ, Hu R, Sullivan L, Galambos E, Fitzpatrick VD, Healy L, Bass MB, Cosenza ME, Afshari CA (2005) Prediction of nephrotoxicant action and identification of candidate toxicity-related biomarkers. Toxicol Pathol 33:343–355

    Article  CAS  PubMed  Google Scholar 

  • Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92:827–839

    Article  CAS  PubMed  Google Scholar 

  • Wang EJ, Syder RD, Fielden MR, Smith RJ, Gu YZ (2008) Validation of putative genomic biomarkers of nephrotoxicity in rats. Toxicology 246:91–100

    Article  CAS  PubMed  Google Scholar 

  • West NA, Severtson SG, Green JL, Dart RC (2015) Trends in abuse and misuse of prescription opioids among older adults. Drug Alcohol Depend 149:117–121

    Article  PubMed  Google Scholar 

  • Yu HS, Oyama T, Isse T, Kitagawa K, Pham TT, Tanaka M, Kawamoto T (2010) Formation of acetaldehyde-derived DNA adducts due to alcohol exposure. Chem Biol Interact 188:367–375

    Article  CAS  PubMed  Google Scholar 

  • Xu F, Fok TF, Yung E, Yin JA, To KF (2000) Antioxidant enzyme activities and antioxidant enzyme gene expression in hyperoxiainduced lung injury in premature rat. HK J Paediatr 5:3–7

  • Zhang Y-T, Zheng Q-S, Pan J, Zheng R-L (2004) Oxidative damage of biomolecules in mouse liver induced by morphine and protected by antioxidants. Basic Clin Pharmacol Toxicol 95:53–58

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Vaidya VS, Brown RP, Zhang J, Rosenzweig BA, Thompson KI, Miller TJ, Bonventre JV, Goering PL (2008) Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury and chromium. Toxicol Sci 101:159–170

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. College of Science, Department of Biochemistry, University of Jeddah, Jeddah, Saudi Arabia

    Haytham A. Ali, Mohamed Afifi, Arwa A Makki & Ammar AL-Farga

  2. Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt

    Haytham A. Ali & Mohamed Afifi

  3. Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt

    Taghred M. Saber

  4. Department of Biochemistry, Faculty of Science, Zagazig University, Zagazig, 44519, Egypt

    A.T. Keshta

  5. College of Science, Department of Biology, University of Jeddah, Jeddah, Saudi Arabia

    Mohammed Baeshen

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Ali, H.A., Afifi, M., Saber, T.M. et al. Neurotoxic, Hepatotoxic and Nephrotoxic Effects of Tramadol Administration in Rats. J Mol Neurosci 70, 1934–1942 (2020). https://doi.org/10.1007/s12031-020-01592-x

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