Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone


Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg), animals received intraperitoneal injections of morphine (5 mg/kg/day) and/or naltrexone (20 mg/kg/day), an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH) concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy.

Nakashima T, Maehara Y, Kohnoe S, Hayashi I, Katsuta Y. Histologic differentiation and chemosensitivity of human head and neck squamous cell carcinomas. Head Neck 1990;12:406-10.

Taguchi T, Nazneen A, Abid M, Razzaque M. Cisplatin- associated nephrotoxicity and pathological events. Contrib Nephrol 2005;148:107-21.

Ishibashi T, Lippard SJ. Telomere loss in cells treated with cisplatin. Proc Natl Acad Sci 1998;95:4219-23.

Ward JM, Fauvie KA. The nephrotoxic effects of< i> cis-diammine-dichloroplatinum (II)(NSC-119875) in male F344 rats. Toxicol Appl Pharmacol 1976;38:535-47.

Ali BH, Al Moundhri MS. Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. Food Cheml Toxicol 2006;44:1173-83.

Abdelrahman AM, Al Salam S, AlMahruqi AS, Mansour MA, Ali BH. Nacetylcysteine improves renal hemodynamics in rats with cisplatin induced nephrotoxicity. J Appl Toxicol 2010;30:15-21.

Khan SA, Priyamvada S, Khan W, Khan S, Farooq N, Yusufi AN. Studies on the protective effect of green tea against cisplatin induced nephrotoxicity. Pharmacol Res 2009;60:382-91.

Baliga R, Zhang Z, Baliga M, Ueda N, Shah SV. In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Kidney Int 1998;53:394-401.

Davis CA, Nick HS, Agarwal A. Manganese superoxide dismutase attenuates cisplatin-induced renal injury: importance of superoxide. J Am Soc Nephrol 2001;12:2683-90.

Lieberthal W, Triaca V, Levine J. Mechanisms of death induced by cisplatin in proximal tubular epithelial cells:apoptosis vs. necrosis. Am J Physiol 1996;270:F700-8.

Kelly K, Meehan SM, Colvin RB, Williams WW, Bonventre JV. Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody. Kidney Int.1999;56:922-31.

Deng J, Kohda Y, Chiao H, Wang Y, Hu X, Hewitt SM, et al. Interleukin-10 inhibits ischemic and cisplatin- induced acute renal injury. Kidney Int 2001;60:2118-28.

Ramesh G, Reeves WB. TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 2002;110:835-42.

Townsend DM, Deng M, Zhang L, Lapus MG, Hanigan MH. Metabolism of cisplatin to a nephrotoxin in proximal tubule cells. J Am Soc Nephrol 2003;14:1-10.

Vallejo R, Barkin RL, Wang VC. Pharmacology of opioids in the treatment of chronic pain syndromes. Pain Physician 2011;14:E343-60.

Lever JR. Opioid Receptors and Ligands: Targets for Cancer Imaging and Therapy. Med Chem 2012;2:142-6.

Gülçın I, Beydemır Ş, Alici HA, Elmastaş M, Büyükokuroğlu ME. In vitro antioxidant properties of morphine. Pharmacol Res 2004;49:59-66.

Bhat RS, Bhaskaran M, Mongia A, Hitosugi N, Singhal PC. Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation. J Leukoc Biol 2004;75:1131-8.

Özmen İ, Nazıroğlu M, Alici HA, Şahin F, Cengiz M, Eren İ. Spinal morphine administration reduces the fatty acid contents in spinal cord and brain by increasing oxidative stress. Neurochem Res 2007;32:19-25.

Sumathi T, Nathiya V, Sakthikumar M. Protective effect of bacoside-A against morphine-induced oxidative stress in rats. Indian J Pharm Sci 2011;73:409-15.

Payabvash S, Beheshtian A, Salmasi AH, Kiumehr S, Ghahremani MH, Tavangar SM, et al. Chronic morphine treatment induces oxidant and apoptotic damage in the mice liver. Life Sci 2006;79:972-80.

Arerangaiah R, Chalasani N, Udager AM, Weber ML, Manivel JC, Griffin RJ, et al. Opioids induce renal abnormalities in tumor-bearing mice. Nephron Exp Nephrol 2007;105:e80-9.

Linner K, Stickney B, Quist H, Sharp B, Portoghese P.The delta1-opioid receptor antagonist, 7- (benzospiroindanyl) naltrexone [correction of 7- benzylspiroindanylnaltrexone], prolongs renal allograft survival in a rat model. Eur J Pharmacol 1998;354:R3-5.

Mutoh J, Ohsawa M, Hisa H. Effect of naloxone on ischemic acute kidney injury in the mouse. Neuropharmacology 2013;71:10-8.

Babu E, Gopalakrishnan V, Sriganth INP,Gopalakrishnan R, Sakthisekaran D. Cisplatin induced nephrotoxicity and the modulating effect of glutathione ester. Mol Cell Biochem 1995;144:7-11.

Kelishomi RB, Ejtemaeemehr S, Tavangar SM, Rahimian R, Mobarakeh JI, Dehpour AR. Morphine is protective against doxorubicin-induced cardiotoxicity in rat. Toxicology 2008;243:96-104.

Atessahin A, Yilmaz S, Karahan I, Ceribasi AO, Karaoglu A. Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology 2005;212:116-23.

Sumathi T, Niranjali Devaraj S. Effect of Bacopa monniera on liver and kidney toxicity in chronic use of opioids. Phytomedicine 2009;16:897-903.

Patel J, Manjappa N, Bhat R, Mehrotra P, Bhaskaran M, Singhal PC. Role of oxidative stress and heme oxygenase activity in morphine-induced glomerular epithelial cell growth. Am J Physiol Renal Physiol 2003;285:F861-9.

Atici S, Cinel I, Cinel L, Doruk N, Eskandari G, Oral U.Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model. J Biosci 2005;30:245-52.

Sumathy T, Subramanian S, Govindasamy S, Balakrishna K, Veluchamy G. Protective role of Bacopa monniera on morphine induced hepatotoxicity in rats. Phytother Res 2001;15:643-5.

Guzmán DC, Vázquez IE, Brizuela NO, Alvarez RG, Mejía GB, García EH, et al. Assessment of oxidative damage induced by acute doses of morphine sulfate in postnatal and adult rat brain. Neurochem Res


Zhou JF, Yan XF, Ruan ZR, Peng FY, Cai D, Yuan H, et al. Heroin abuse and nitric oxide, oxidation, peroxidation, lipoperoxidation. Biomed Environ Sci 2000;13:139.

Zhang YT, Zheng QS, Pan J, Zheng RL. Oxidative damage of biomolecules in mouse liver induced by morphine and protected by antioxidants. Basic Clin Pharmacol Toxicol 2004;95:53-8.

Faubel S, Lewis EC, Reznikov L, Ljubanovic D, Hoke TS, Somerset H, et al. Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1β, IL-18, IL-6, and neutrophil infiltration in the kidney. J Pharmacol Exp Ther 2007;322:8-15.

Sawaya BE, Deshmane SL, Mukerjee R, Fan S, Khalili K.TNF Alpha Production in Morphine-Treated Human Neural Cells Is NF-κB-Dependent. J Neuroimmune Pharmacol 2009;4:140-9.

Deroee AF, Nezami BG, Mehr SE, Hosseini R, Salmasi AH, Talab SS, et al. Cholestasis induced nephrotoxicity: the role of endogenous opioids. Life Sci 2010;86:488-92.

IssueVol 54, No 7 (2016) QRcode
Cisplatin Morphine Naltrexone Antioxidant Nephrotoxicity Immunomodulatory

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Aminian A, Javadi S, Rahimian R, Dehpour AR, Asadi Amoli F, Moghaddas P, Ejtemaei Mehr S. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone. Acta Med Iran. 54(7):422-429.