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Tramadol Promotes Oxidative Stress, Fibrosis, Apoptosis, Ultrastructural and Biochemical alterations in the Adrenal Cortex of Adult Male Rat with Possible Reversibility after Withdrawal

Published online by Cambridge University Press:  05 May 2020

Amany Mohamed Shalaby Open the ORCID record for Amany Mohamed Shalaby [Opens in a new window] ,
Adel Mohamed Aboregela ,
Mohamed Ali Alabiad  and
Dina Fouad El Shaer
Amany Mohamed Shalaby*
Affiliation:
Histology and Cell Biology Department, Faculty of Medicine, Tanta University, Tanta31527, Egypt
Adel Mohamed Aboregela
Affiliation:
Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig44519, Egypt Basic Medical Sciences Department, College of Medicine, Bisha University, Bisha, Kingdom of Saudi Arabia
Mohamed Ali Alabiad
Affiliation:
Pathology Department, Faculty of Medicine, Zagazig University, Zagazig44519, Egypt
Dina Fouad El Shaer
Affiliation:
Histology and Cell Biology Department, Faculty of Medicine, Tanta University, Tanta31527, Egypt
*
*Author for correspondence: Amany Mohamed Shalaby, E-mail: [email protected]
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Abstract

Tramadol is a centrally acting analgesic drug, used for the management of moderate to severe pain in a variety of diseases. The long-term use of tramadol can induce endocrinopathy. This study aimed to evaluate the effect of tramadol dependence on the adrenal cortex and the effect of its withdrawal. Thirty adult male rats were divided into three experimental groups: the control group, the tramadol-dependent group that received increasing therapeutic doses of tramadol orally for 1 month, and the recovery group that received tramadol in a dose and duration similar to the previous group followed by a withdrawal period for another month. Specimens from the adrenal cortex were processed for histological, immunohistochemical, enzyme assay, and quantitative real-time PCR (RT-qPCR) studies. Tramadol induced a significant increase in malondialdehyde level and a significant decrease in the levels of glutathione peroxidase and superoxide dismutase. A significant decrease in the levels of adrenocorticotrophic hormones, aldosterone, cortisol, corticosterone, and dehydroepiandrosterone sulfate was also detected. Severe histopathological changes in the adrenal cortex were demonstrated in the form of disturbed architecture, swollen cells, and shrunken cells with pyknotic nuclei. Inflammatory cellular infiltration and variable-sized homogenized areas were also detected. A significant increase in P53 and Bax immunoreaction was detected and confirmed by RT-qPCR. The ultrastructural examination showed irregular, shrunken adrenocorticocytes with dense nuclei. Dilated smooth endoplasmic reticulum, mitochondria with disrupted cristae, and numerous coalesced lipid droplets were also demonstrated. All these changes started to return to normal after the withdrawal of tramadol. Thus, it was confirmed that the long-term use of tramadol can induce severe adrenal changes with subsequent insufficiency.

Keywords

adrenal cortexelectron microscopyoxidative stressRT-qPCRtramadol
Type
Biological Applications
Information
Microscopy and Microanalysis , Volume 26 , Issue 3 , June 2020 , pp. 509 - 523
Copyright
Copyright © Microscopy Society of America 2020

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References

Abdelaleem, SA, Hassan, OA, Ahmed, RF, Zenhom, NM, Rifaai, RA & El-Tahawy, NF (2017). Tramadol induced adrenal insufficiency: Histological, immunohistochemical, ultrastructural, and biochemical genetic experimental study. Toxicol Hyg 2017, 9815853.Google ScholarPubMed
Abdullah, BA (2018). Histological and molecular studies of the effects of tramadol on brain, liver and kidney of adult rabbits. Iraqi J Agric Sci 49(6), 1083–1089.Google Scholar
Ahmed, MA & Kurkar, A (2014). Effects of opioid (tramadol) treatment on testicular functions in adult male rats: The role of nitric oxide and oxidative stress. Clin Exp Pharmacol Physiol 41(4), 317–323.CrossRefGoogle ScholarPubMed
Badawy, SM, Hammad, SA, Amin, SA, Zanaty, AW, Mohamed, RH & Aiad, HA (2014). Effects of dependence of tramadol, diazepam and their combination on the brain of Albino rats: Biochemical, histological and immunohistochemical study. J Forensic Med Clin Toxicol 23, 139–147.Google Scholar
Baghishani, F, Mohammadipour, A, Hosseinzadeh, H, Hosseini, M & Ebrahimzadeh-bideskan, A (2018). The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin. Metab Brain Dis 1, 907–916.CrossRefGoogle 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(2), 164–170.CrossRefGoogle ScholarPubMed
Bassiony, MM, Salah El-Deen, GM, Yousef, U, Raya, Y, Abdel-Ghani, MM, El-Gohari, H & Atwa, SA (2015). Adolescent tramadol use and abuse in Egypt. Am J Drug Alcohol Abuse 41, 206–211.CrossRefGoogle ScholarPubMed
Beck, SG & Handa, RJ (2004). Dehydroepiandrosterone (DHEA): A misunderstood adrenal hormone and spine-tingling neurosteroid? Endocrinology 145(3), 1039–1041.CrossRefGoogle ScholarPubMed
Ben Ammar, H, Jomli, R, Rihab, E, Moula, O, Bouasker, A & Ghachem, R (2013). 2856 – Tramadol dependence in a patient with no previous substance history. Eur Psychiatry 28, 1.Google Scholar
Daniell, HW (2006). DHEAS deficiency during consumption of sustained action prescribed opioids: Evidence for opioid induced inhibition of adrenal androgen production. J Pain 7(12), 901–907.CrossRefGoogle ScholarPubMed
Dawson-Saunders, B & Trapp, RG (2001). Section 5.6: Proportions when the same group is measured twice. In Basic & Clinical Biostatistics: Lange Medical Book, Dawson, B, Trapp, RG & Trapp, R (Eds.), 3rd ed., pp. 115–118. New York, Montreal: McGraw-Hill Book Co.Google Scholar
Debono, M, Chan, S, Rolfe, C & Jones, TH (2011). Tramadol-induced adrenal insufficiency. Eur J Clin Pharmacol 67, 865–867.CrossRefGoogle ScholarPubMed
Dickman, A (2007). Tramadol: A review of this atypical opioid. Eur J Palliat Care 14, 181–185.Google Scholar
El-Gaafarawi, II (2006). Biochemical toxicity induced by tramadol administration in male rats. Egypt J Hosp Med 23, 353–362.Google Scholar
Elshennawy, WW & Aboelwafa, RH (2011). Structural and ultrastructural alterations in mammalian adrenal cortex under influence of steroidogenesis inhibitors drug. J Am Sci 7(8), 567–576.Google Scholar
Everds, NE, Snyder, PW, Bailey, KL, Bolon, B, Creasy, DM, Foley, GL, Rosol, TJ & Sellers, T (2013). Interpreting stress responses during routine toxicity studies: A review of the biology, impact, and assessment. Toxicol Pathol 41(4), 560–614.CrossRefGoogle ScholarPubMed
Ghoneim, FM, Khalaf, HA, Elsamanoudy, AZ & Helaly, AN (2014). Effect of chronic usage of tramadol on motor cerebral cortex and testicular tissues of adult male albino rats and the effect of its withdrawal: Histological, immunohistochemical and biochemical study. Int J Clin Exp Pathol 7(11), 7323.Google ScholarPubMed
Gong, S, Miao, YL, Jiao, GZ, Sun, MJ, Li, H, Lin, J, Luo, MJ & Tan, JH (2015). Dynamics and correlation of serum cortisol and corticosterone under different physiological or stressful conditions in mice. PLoS ONE 10, 2.Google ScholarPubMed
Hussein, SA, Abdel Aal, SA & Ismail, HK (2017). Effect of tramadol drug on some biochemical and immunological parameters in Albino male rats: Evaluation of possible reversal following its withdrawal. Benha Veterinary Med J 33(2), 418–429.CrossRefGoogle Scholar
Iqbal, M, Sharma, SD, Rezazadeh, H, Hasan, N, Abdulla, M & Athar, MJRR (1996). Glutathione metabolizing enzymes and oxidative stress in ferric nitrilotriacetate mediated hepatic injury. Redox Rep 2(6), 385–391.CrossRefGoogle ScholarPubMed
Kajita, K, Mori, I, Masahiro, TI, Morita, H & Ishizuka, T (2015). Anti-Obesity Effects of Androgens, Dehydroepiandrosterone (DHEA) and Testosterone, Treatment of Type 2 Diabetes, p. 295. Colleen Croniger, IntechOpen. https://www.intechopen.com/profiles/55053/colleen-croniger.Google Scholar
Kakkar, P, Das, B & Viswanathan, PN (1984). A modified spectrophotometric assay of superoxide dismutase. Ind J Biochem Biophys 21, 130–132.Google ScholarPubMed
Karthikeyan, M, Arunakaran, J & Balasubramanian, K (2009). The effect of prolactin and corticosteroid on insulin binding to rat Leydig cells. Reprod Biol 9, 189–194.CrossRefGoogle Scholar
Kassab, AA, Aboregela, AM & Shalaby, AM (2020). Edaravone attenuates lung injury in a hind limb ischemia-reperfusion rat model: A histological, immunohistochemical and biochemical study. Ann Anat 1(228), 151433.CrossRefGoogle Scholar
Khalaf, HA, Ghoneim, FM, Arafat, EA & Mahmoud, EH (2017). Histological effect of nicotine on adrenal zona fasciculata and the effect of grape seed extract with or without withdrawal of nicotine. J Microsc Ultrastruct 5(3), 123–131.CrossRefGoogle ScholarPubMed
Khalil, MS (2015). Vitamin D3 may ameliorate the ketoconazole induced adrenal injury: Histological and immunohistochemical studies on Albino rats. Acta Histochem Cytochem 48(4), 103–113.CrossRefGoogle ScholarPubMed
Khan, MR & Younus, T (2011). Prevention of CCl4-induced oxidative damage in adrenal gland by Digera muricata extract in rat. Pak J Pharm Sci 24(4), 469–473.Google Scholar
Khodeary, MF, AI, SED & El Kholy, SM (2010). A histopathological and immunohistochemical study of adult rat brain after long-term exposure to amadol (tramadol hydrochloride). Mansoura J Forensic Med Clin Toxicol 18, 1–24.CrossRefGoogle Scholar
Kiernan, AJ (2008). Histological and Histochemical Methods: Theory and Practice, 4th ed., p. 274. Bloxham, UK: Scion.Google Scholar
Lanier, RK, Lofwall, MR, Mintzer, MZ, Bigelow, GE & Strain, EC (2010). Physical dependence potential of daily tramadol dosing in humans. Psychopharmacology 211(4), 457–466.CrossRefGoogle ScholarPubMed
Matsumoto, R, Fukuoka, H, Iguchi, G, Odake, Y, Yoshida, K, Bando, H, Suda, K, Nishizawa, H, Takahashi, M, Yamada, S & Ogawa, W (2015). Accelerated telomere shortening in acromegaly: IGF-I induces telomere shortening and cellular senescence. PLoS ONE 10(10), e0140189.CrossRefGoogle ScholarPubMed
Mc Diarmid, T & Mackler, L (2005). What is the addiction risk associated with tramadol? J Fam Pract 54(1), 72–74.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.CrossRefGoogle ScholarPubMed
Mohamed, TM, Ghaffar, HM & El Husseiny, RM (2015). Effects of tramadol, clonazepam, and their combination on brain mitochondrial complexes. Toxicol Ind Health 31(12), 1325–1333.CrossRefGoogle ScholarPubMed
Mohandas, J, Marshall, JJ, Duggin, GG, Horvath, JS & Tiller, DJ (1984). Differential distribution of glutathione and glutathione-related enzymes in rabbit kidney: Possible implications in analgesic nephropathy. Biochem Pharmacol 33(11), 1801–1807.CrossRefGoogle ScholarPubMed
Nna, VU & Osim, EE (2017). Testicular toxicity following separate and combined administration of PDE 5 inhibitors and opioid: Assessment of recovery following their withdrawal. Andrologia 49(6), e12669.CrossRefGoogle ScholarPubMed
Oltmanns, KM, Fehm, HL & Peters, A (2005). Chronic fentanyl application induces adrenocortical insufficiency. J Intern Med 257(5), 478–480.CrossRefGoogle ScholarPubMed
Osman, HA (2010). Morphological evaluation on the protective effect of curcumin on nicotine induced histological changes of the adrenal cortex in mice. Egypt J Histol 33, 552–559.Google Scholar
Piyathilaka, MA, Pathmalal, MM, Tennekoon, KH, De Silva, BG, Samarakoon, SR & Chanthirika, S (2015). Microcystin-LR-induced cytotoxicity and apoptosis in human embryonic kidney and human kidney adenocarcinoma cell lines. Microbiology 161(4), 819–828.CrossRefGoogle ScholarPubMed
Popovic, M, Janicijevic-Hudomal, S, Kaurinovic, B, Rasic, J, Trivic, M & Vojnović, M (2009). Antioxidant effects of some drugs on immobilization stress combined with cold restraint stress. Molecules 14, 4505–4516.CrossRefGoogle ScholarPubMed
Rabei, HM (2011). The immunological and histopathological changes of tramadol, tramadol/acetaminophen and acetaminophen in male Albino rats “Comparative study”. Egypt J Hosp Med 45, 477–503.Google Scholar
Ragab, IK & Mohamed, HZ (2017). Histological changes of the adult albino rats entorhinal cortex under the effect of tramadol administration: Histological and morphometric study. Alex J Med 53(2), 123–133.CrossRefGoogle Scholar
Sakr, SM & Sabry, SA (2016). Midazolam impact on the ultrastructural characteristic of mice adrenal cortex. Merit Res J Med Med Sci 4(1), 059–067.Google Scholar
Sayed, HY & Zidan, AH (2016). Histopathological and biochemical effects of acute and chronic tramadol drug toxicity on liver, kidney, and testicular function in adult male albino rats. J Forensic 1(2), 41.Google Scholar
Seyfried, O & Hester, J (2012). Opioid and endocrine dysfunction. Br J Pain 6(1), 17–24.CrossRefGoogle ScholarPubMed
Shadnia, S, Soltaninejad, K, Heydari, K, Sasanian, G & Abdollahi, M (2008). Tramadol intoxication: A review of 114 cases. Hum Exp Toxicol 27, 201–205.CrossRefGoogle ScholarPubMed
Shalaby, AM & El Shaer, DF (2019). Lycopene protects against renal cortical damage induced by nandrolone decanoate in adult male rats. Ann Anat 224, 142–152.CrossRefGoogle ScholarPubMed
Simeon, GG & Abbey, ST (2018). Some marker enzymes and histological alteration on the administration of tramadol hydrochloride on rat liver. Modern Res Inflamm 7, 9–20.CrossRefGoogle Scholar
Singh, N, Snyder, RW & Krishnamurthy, M (2014). An under-recognized and under-reported cause of adrenal insufficiency. Int J Case Rep Med 10, 1–4.Google Scholar
Soliman, HM, El-Haleem, MA & El Tarhouny, SA (2015). Histomorphometrical and electron microscopic study of adrenocorticocytes following surgically induced extrahepatic biliary obstruction in adult female Albino rats. Folia Biol 61(1), 14.Google ScholarPubMed
Thomas, M, Keramidas, M, Monchaux, E & Feige, JJ (2004). Dual hormonal regulation of endocrine tissue mass and vasculature by adrenocorticotropin in the adrenal cortex. Endocrinology 145, 4320–4329.CrossRefGoogle ScholarPubMed
Vazzana, M, Andreani, T, Fangueiro, J, Faggio, C, Silva, C, Santini, A, Garcia, ML, Silva, AM & Souto, EB (2015). Tramadol hydrochloride: Pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother 70, 234–238.CrossRefGoogle ScholarPubMed
Vuong, C, Van Uum, SHM, O'Dell, LE, Lutfy, K & Friedman, TC (2010). The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev 31, 98–132.CrossRefGoogle ScholarPubMed
Willenberg, HS, Schinner, S & Ansurudeen, I (2008). New mechanisms to control aldosterone synthesis. Horm Metab Res 40(07), 435–441.CrossRefGoogle ScholarPubMed
Woods, A & Stirling, J (2008) Electron microscope. In Theory and Practice of Histological Techniques, Bancroft, J & Gamble, M (Eds.), p. 600. Philadelphia, PA: Churchill Livingstone/Elsevier.Google Scholar
Zhang, H & Liu, Z (2013). The investigation of tramadol dependence with no history of substance abuse: A cross-sectional survey of spontaneously reported cases in Guangzhou City, China. Biomed Res Int 2013, 283425.CrossRefGoogle ScholarPubMed