Effect of Exercise on Morphine-Induced Toxicity in Rat Liver and Kidney

Document Type : Original Article


1 Professor of Occupational Health Department of Occupational Health, Physiology Research Center & Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

2 Professor of Physiology.Physiology Research Center & Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

3 Assistant Professor of Physiology. Department of Physiology & Faculty of Medicine, Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

4 Associate Professor of Pathology.Department of Pathology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Iran.

5 M.Sc. of Bioanformatic.Physiology Research Center & Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.


Background and Objective: Morphine induces adverse effect in many organs. It has been known that moderate exercise reduces oxidative stress. The present study was undertaken to evaluate the effect of exercise on morphine-produced toxicity in rat liver and kidney.
Subjects and Methods:  Adult male rats were randomly divided in 4 groups including: (1) morphine-treated, (2) morphine-treated+exercise, (3) vehicle (normal saine) treated, (4) vehicle treated+exercise. Animals in groups of 1 and 2 received morphine (ip) two times per day for 5 consecutive days. 1st day 5mg/kg, 2nd day10 mg/kg, 3rd day 20mg/kg, 4th day 40mg/kg and 5th 50mg/kg. Rats in groups of 3 and 4 received vehicle only. The animals in groups of 2 and 4 were participated in the treadmill exercise sessions (1 h at speed 17m/min) for 10 consecutive days. 24 h later, the animals were killed with overdose of sodium pentobarbital. Blood was collected for determination of ALT, AST, ALP, BUN and creatinine. Liver and kidney tissues were removed, fixed and processed for light microscopy. Ten animals were used for each group.
Results: Biochemical and histopathological observations indicated that morphine produced injury in the liver and the kidney. Exercise reduced morphine -induced toxicity (P<0.05).
Conclusion: Morphine- induced toxicity in rat liver and kidney. Execise protected liver and kidney against morphine-induced toxicity. Blocking of oxidative damage by exercise may be a useful strategy for preventing morphine adverse effects.


1-MacPherson RD. The pharmacological basis of contemporary pain management. Pharmacol Ther 2000;88(2):163-85.
2-Stain-Texier F, Sandouk P, Scherrmann JM. Intestinal absorption and stability of morphine 6-glucuronide in different physiological compartments of  the  rat. Drug Metab Dispos 1998;26(5):383-7.
3-Pacifici GM, Bencini C, Rane A. Presystemic glucuronidation of morphine in humans and rhesus monkeys: Subcellular distribution of the UDP-glucuronyltransferase in the liver and intestine. Xenobiotica 1986;16(2):123-8.
‌4-Yue Q, von Bahr C, Odar-Cederlöf  I, Säwe JGlucuronidation of codeine and morphine in human liver and kidney microsomes: effect of inhibitors. Pharmacol Toxicol.1990;66(3):221-6.
5-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(2):245-52.
6-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(2):53-8.
7-Ahmadizadeh M, Razi Jalali M. Effect of vitamin C on morphine-induced liver and respiratory epithelial cells damage in rats. Biochem Cell Arch 2006;6(1):29-36.
8-Toki S, Yamano S. [Production of morphinone as a metabolite of morphine and its physiological role].Yakugaku Zasshi 1999;119(4):249-67. [Article in Japanese]
9-Nagamatsu K, Kido Y, Terao Y, Ishida T, Toki S. Studies on the mechanism of covalent binding of morphine metabolites to proteins in mouse. Drug Metab Dispos 1983;11(3):190-4.
10-TodakaT ,  IshidaT,  Kita  H,  Narimatsu S,  Yamano S. Bioactivation of morphine in human liver: isolation and identification of morphinone, a toxic metabolite. Biol Pharm Bull 2005;28(7):1275-80.
11-Sumathi T,Niranjali Devaraj S. Effect of Bacopa monniera on liver and kidney toxicity in chronic use of opioids. Phytomedicine 2009;16(10):897-903.
12-Khazaeinia T,  Ramsey AA, Tam YK. The effects of exercise on the pharmacokinetics of drugs. J Pharm Pharm Sci 2000;3(3):292-302.
13-van Baak MA. Influence of exercise on the pharmacokinetics of drugs. Clin Pharmacokinet 1990;19(1):32-43.
14-Shing CM, Peake JM, Ahern SM, Strobel NA, Wilson G, Jenkins DG, et al. The effect of consecutive days of exercise on markers of oxidative stress. Appl Physiol Nutr Metab 2007;32(4):677-85.
15-Yilmaz N, Erel O, Hazer M, Bagci C, Namiduru E, Gul E. Biochemical  assessments of retinol, alpha-tocopherol, pyridoxal--5-phosphate oxidative stress index and total antioxidant status in adolescent professional basketball players and sedentary controls. Int J Adolesc Med Health 2007;19(2):177-86.
16-Asghar M, George L, Lokhandwala MF. Exercise decreases oxidative stress and inflammation and restores renal dopamine D1 receptor function in old rats. Am J Physiol Renal Physiol 2007;293(3):F914-9.
17-Kakarla P, Vadluri G, Reddy Kesireddy S. Response of hepatic antioxidant system to exercise training in aging female rat. J Exp Zool A Comp Exp Biol 2005;303(3):203-8.
18- Alaei H, Borjeian L, Azizi M, Orian S. Pourshanazari A, Hanninen O. Treadmill running reverses retention deficit induced by morphine. Eur J Pharmacol 2006;536(1-2):138-41.
19-Eisenstein SA, Holmes PV. Chronic and voluntary exercise enhances learning of conditioned place preference to morphine in rats. Pharmacol Biochem Behav 2007;86(4):607-15.
20-Jornot L, Junod AF. Response of human endothelial cell antioxidant enzymes to hyperoxia. Am J Respir Cell Mol Biol 1992;6:107-115.
21-Stellar JR, Stellar E. The neurobiology of motivation and reward. New York: Springer-Verlag; 1985. p. 962-3.
22-Hao Y, Yang JY, Guo M, Wu CF, Wu MF. Morphine decreases extracellular levels of glutamate in the anterior cingulate cortex: an in vivo microdialysis study in freely moving rats. Brain Res 2005;1040(1-2):191-6.
23-Mallikarjuna K, Nishanth K, Hou CW, Kuo CH, Sathyavelu Reddy K. Effect of exercise training on ethanol-induced oxidative damage in aged rats. Alcohol 2009;43(1):59-64.
24-Navarro A, Gomez C, López-Cepero JM, Boveris A.  Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol Regul Integr Comp Physiol 2004;286(3): R505-11
25-Koltyn KF. Analgesia following exercise: a review. Sports Med 2000;29(2):85-98.
 27-Hosseini M, Alaei HA, Naderi A, Sharifi MR, Zahed R. Treadmill exercise reduces self-administration of morphine in male rats. Pathophysiology 2009;16(1):3-7.
28-Sadipour KH, Sarkaki AR, Badavi M, Alaei HA. Effect of short-term forced exercise on naloxone induced withdrawal symptoms in morphine addicted male rats. Armaghane Danesh 2008;12(4):73-80.