Effects of Forced Exercise on Withdrawal Syndrome, Brain Hippocampus Neurons Count and Level of Serum Corticosterone in Morphine Addicted Male Rats


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

2 M.Sc. Student in Physiology.Department of Physiology & Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

3 Associate Professor of Anatomy. Department of Anatomy & Physiology Research Center & Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

4 Assistant Professor of Physiology. Department of Physiology & Faculty of Medicine, Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, 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: addiction to morphine impairs the behavioral and cognitive performances. The aim of the present study was to evaluate the effects of forced exercise (treadmill) on withdrawal signs after morphine deprivation, serum corticostrone level,and hippocampusneurons count in brain hemisphers in rats addicted to morphine.
Subjects and Methods: Adult male Wistar rats were divided into five groups with 10 in each: 1) exercised control (C+E), 2) sham exercised control (C+Sh.E), 3) addicted (A), 4) exercised addicted (A+E), and 5) sham-exercised addicted (A+Sh.E). Withdrawal signs such as number of jumping, teeth chattering, wet-dog shaking, defecation, body scratching, and standingas number of were counted during 30 minutes after naloxone administration. Animals in exercised groups ran on treadmill one hour daily from 9-10 Am in the morning for ten consecutive  days. Sham-exercised groups passed same times on turned off treadmill while its shock delivered system was turned on. At the end of experiments serum corticostrone level and hippocampus neurons count were done after decapitation the animals in all groups. The data were analyzed with one-way ANOVA that followed by LSD post hoc test. The differences between groups were accepted as significant with P value less than 0.05.
Results: Addiction to morphine increased withdrawal signs and corticostrone secretion significantly and reduced hipocampal neurons in brain, All off which were significant. Forced exercise could inhibit certain withdrawal signs induced by morphine deprivation in addicted rats while could not reverse increased corticostrone level and decreased hippocampus neurons.
Conclusion: Despite of useful effects of forced exercise on health conditions and especially cognition during aging, it would cause impair severely some neurobehavioral and hormonal disorders in addicted rats to morphine.


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.
2-Anderson G, Sjogren  P, Hansen SH, Jensen  NH, Christrup L. Pharmacological consequences of long-term morphine treatment in patients with cancer and chronic non-malignant pain. Eur J Pain 2004;8:263-71.
3-Atici S, Cinel L, Cinel I, Doruk N, Aktekin M,  Akca A, Camdeviren H, Oral U. Opioid neurotoxicity: comparison of morphine and  tramadol in an experimental rat model. Int J Neurosci 2004; 114:1001-11.
4-Correia MA, Wong JS, Soliven E. Morphine metabolism revisited: I. Metabolic activation of morphine to a reactive species in rats. Chem Biol Interact 1984;49:255-68.
5-Toki S ,Yamano S. Production of morphinone as a metabolite of morphine and its physiological role. Yakugaku Zasshi 1999;119:249-67. [Japanese]
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; 95:53-8.
7-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.
8-Armstrong  SC, Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: Theory and clinical reality, part II . Psychosomatics 2003:44:515-20.
 9-Glogowska-Szelag   J, Plewka  A, Kaminski  M, Gorski  J, Kajdaniuk  D, Nowak M , et al. Activity of liver cytochrome p-450-dependent monooxygenase system in morphine-dependent rats. Folia Biol (Praha) 1996;42 :113-5. 
10-Dunlap CE, Leslie FM. Effect of ascorbate on the toxicity of morphine in mice. Neuropharmcology 1985;24:797-804.
11-Ahmadizadeh M, Razi Jalali M.  Effect of vitamin C on morphine-induced liver and respiratory epithelial cells damage in rats. Biochem Cell Arch 2006;6:29-36.
12- Alaei H, Borjeian L, Azizi M, Orian S, Pourshanazari A, Hanninen O. Treadmill running reverses retention deficit induced by morphine. Eur.J Pharmacol 2006;536:138-141.
13- Acevedo EO, Kraemer RR, Kamimori GH, Durand RJ, Johnson LG, Castracane VD. Stress hormones, effort sense, and perceptions of stress during incremental exercise: an exploratory investigation. J Strength Cond Res 2007;21:283-8.
14-Pushpalatha K, Nishanth K, Sathyavelu Reddy K. Myocardial antioxidant status and oxidative  stress after combined action of exercise training and ethanol in two different age groups of male albino rats. Acta Biol Hung 2007;58:173-85.
15-Karanth J, Kumar R, Jeevaratnam K.  Response of antioxidant system in rats to dietary fat and physical activity. Indian J Physiol Pharmacol 2004;48:446-52. 

16-Kaczor JJ, Hall JE, Payne E, Tarnopolsky MA. Low intensity training decreases markers of oxidative stress in skeletal muscle of mdx mice. Free Radic Biol Med 2007;43:145-54.

17-Duclos M, Martin C, Malgat M, Mazat JP, Chaouloff  F, Mormede P, et al. Relationships between muscle mitochondrial metabolism and stress-induced corticosterone variations in rats. Pflugers Arch 2001;443:218-26.
 18.     Dudgeon WD, Phillips KD, Durstine JL, Burgess SE, Lyerly GW, Davis JM, et al.  Individual exercise sessions alter circulating hormones and cytokines in HIV-infected men. Appl Physiol Nutr Metab 2010;35:560-8.
19-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:R505-11.
20-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:F914-9.
21-Eisenstein SA, Holmes PV. Chronic and voluntary exercise enhances learning of conditioned place preference to morphine in rats. Pharmacol Biochem Behav 2007;86:607-15.
22-Ang ET, Dawe GS, Wong PT, Moochhala S, Ng YK. Alterations in spatial learning and memory after forced exercise. Brain Res 2006;1113:186-93.
23-Thoren  P, Floras JS, Haffmann P, Seals DR. Endorphins and exercise: physiology mechanisms and clinical implications. Med Sci Sports Exerc 1990;22:417-28.
24-Stain-Texier F, Sandouk P, Scherrmann JM. Intestinal absorption and stability of morphine 6-glucuronide in different physiological compartments of rat. Drug Metab Dispos 1998;26:383-7.
25-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;1040:191-6.
26-Smith MA, Yancey DL. Sensitivity to the effect of opioids in rats with free access to exercise wheels: mu-opioid tolerance and physical dependence. Psychopharmacology (Berl) 2003;168:426-34.
27-Hosseinzadeh H, Nourbakhsh M. Effect of Rosmarinus officinalis L. aerial parts exteract on morphine withdrawal syndrome in mice.Phytother Res2003;17:938-41.
28-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;16:123-8.
29-Sumathi T, Niranjali Devaraj S. Effect of Bacopa monniera on liver and kidney toxicity in chronic use of opioids.  Phytomedicine 2009;16:897-903.
30-Dave RS, Khalili K. Morphine treatment of human monocyte-derived macrophages induces differential miRNA and protein expression: impact on inflammation and oxidative stress in the central nervous system. J Cell Biochem 2010;110:834-45.
31-Calderon-Guzman D, Osnaya-Brizuela N, Garcia-Alvarez R, Hernandez-Garcia E, Juarez-Olguin H.  Oxidative stress induced by morphine in brain of rats fed with a protein deficient diet. Hum Exp Toxicol 2009;28:577-82.
32-Vuckovic MG, Li Q, Fisher B, Nacca A, Leahy RM, Walsh JP, et al. Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: in vivo imaging with [18F]fallypride. Mov Disord             2010;25:2777-84.
33-Muhammad AB, Lokhandwala MF, Banday AA. Exercise reduces oxidative stress but does not alleviate hyperinsulinemia or renal dopamine D1 receptor dysfunction in obese rats. Am J Physiol Renal Physiol 2011;300:F98-104.
34-Zigmond MJ, Cameron JL, Leak RK, Mirnics K, Russell VA, Smeyne RJ, et al. Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency. Parkinsonism Relat Disord 2009;15:S42-5.
35-Wahl P, Zinner C, Achtzehn S, Bloch W, Mester J.  Effect of  high- and  low-intensity exercise and metabolic acidosis on levels of GH, IGF-I, IGFBP-3 and cortisol. Growth Horm IGF Res 2010;20:380-5.
36-Rahman ZA, Abdullah N, Singh R, Sosroseno W.  Effect of acute exercise on the levels of salivary cortisol, tumor necrosis factor-alpha and nitric oxide. J Oral Sci 2010;52:133-6.
37-Rojas Vega S, Struder HK, Vera Wahrmann B, Schmidt A, Bloch W, Hollmann W. Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans. Brain Res 2006;1121:59-65.
38-Malinowski K, Shock EJ, Rochelle P, Kearns CF, Guirnalda PD, McKeever KH.  Plasma beta-endorphin, cortisol and immune responses to acute exercise are altered by age and exercise training in horses. Equine Vet J Suppl 2006;(36):267-73.
39-Kanaley JA, Weltman JY, Pieper KS, Weltman A, Hartman ML.  Cortisol and growth hormone responses to exercise at different times of day. J Clin Endocrinol Metab 2001;86:2881-9.
40-Kamei T, Toriumi Y, Kimura H, Ohno S, Kumano H, Kimura K. Decrease in serum cortisol during yoga exercise is correlated with alpha wave activation. Percept Mot Skills 2000;90:1027-32.
41-Lou SJ,  Liu JY, Chang H, Chen PJ. Hippocampal neurogenesis and gene expression depend on exercise intensity in juvenile rats. Brain Res 2008;1210:48-55.
42-van Praag H. Neurogenesis and exercise: past and future directions. Neuromolecular Med 2008;10:128-40.
43-Chen L, Gong S, Shan LD, Xu WP, Zhang YJ, Guo SY, et al.  Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats. Neurosci Bull 2006;22:1-6.