Effect of forced treadmill exercise and blocking of opioid receptors with naloxone on memory in male rats


1 Department of Biology, Falavarjan Branch, Islamic Azad University, Isfahan, Iran

2 Department of Physiology, School of Medicine; Applied Physiology Research Center; Biosensor Research Center, Isfahan University of Medical Sciences, Isfahan, Iran


Background: The forced treadmill running can influence the opioid contents of the brain, through both effects of exercise and the effects of stress caused by coercion. Since opioids can cause negative effects on brain functions, this study aimed to evaluate the effect of forced treadmill exercise and blocking of opioid receptors with naloxone on memory in male rats.
Materials and Methods: Experimental groups were the control, the exercise, the naloxone, and the naloxone exercise. The exercise program was treadmill running at 22 m/min at 0° inclination for 50 min/day, 6 days/week, for 4 weeks. Naloxone (1 mg/kg) was injected 5 min before the treadmill running. Morris water maze and passive avoidance learning tests were used for evaluation of memory. Acquisition phase of both tests was performed before interventions, and memory was evaluated 1-day and 1-week after the last session of exercise and treatments.
Results: Our data showed that forced exercise impaired performance in passive avoidance learning test (P < 0.05 and P <0.01, 1-day, and 1-week after the last session of exercise and treatments, respectively). Spatial memory was only impaired after 1-week in the exercise group. Naloxone had no significant effect on memory in the control group. However, it improved memory in the exercise group, as there was no significant difference between the control and the naloxone exercise in both tests.
Conclusion: The data correspond to the possibility that opioidergic system may have mediatory roles in exercise-induced responses in forced exercise. These roles are likely harmful for memory.


Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, et al. The runner's high: Opioidergic mechanisms in the human brain. Cereb Cortex 2008;18:2523-31.  Back to cited text no. 1
Thorén P, Floras JS, Hoffmann P, Seals DR. Endorphins and exercise: Physiological mechanisms and clinical implications. Med Sci Sports Exerc 1990;22:417-28.  Back to cited text no. 2
Koyuncuoglu H, Nurten A, Enginar N, Ozerman B, Kara I. The effects of different 4-aminopyridine and morphine combinations on the intensity of morphine abstinence. Pharmacol Res 2001;43:245-50.  Back to cited text no. 3
Koltyn KF. Analgesia following exercise: A review. Sports Med 2000;29:85-98.  Back to cited text no. 4
Classen W, Mondadori C. Facilitation or inhibition of memory by morphine: A question of experimental parameters. Experientia 1984;40:506-9.  Back to cited text no. 5
Alaei H, Borjeian L, Azizi M, Orian S, Pourshanazari A, Hanninen O. Treadmill running reverses retention deficit induced by morphine. Eur J Pharmacol 2006;536:138-41.  Back to cited text no. 6
Azizi-Malekabadi H, Alaei H, Oryan S. The effects of exercise (treadmill running) on glutamate concentration variation of hippocampal dentate gyrus in the intact and morphine dependent male rats. Iran J Basic Med Sci 2007;32:250-9.  Back to cited text no. 7
Izquierdo I. Effect of naloxone and morphine on various forms of memory in the rat: Possible role of engogenous opiate mechanisms in memory consolidation. Psychopharmacology (Berl) 1979;66:199-203.  Back to cited text no. 8
Poulsen FR, Meyer M, Rasmussen JZ. Generation of new nerve cells in the adult human brain. Ugeskr Laeger 2003;165:1443-7.  Back to cited text no. 9
Hasanein P, Ghafari-Vahed M. Fatty acid amide hydrolase inhibitor URB597 prevented tolerance and cognitive deficits induced by chronic morphine administration in rats. Behav Pharmacol 2015; [Epub ahead of print].  Back to cited text no. 10
McNamara RK, Skelton RW. Pretraining morphine impairs acquisition and performance in the morris water maze: Motivation reduction rather than amnesia. Psychobiology 1991;19:313-22.  Back to cited text no. 11
McNamara RK, Skelton RW. Pharmacological dissociation between the spatial learning deficits produced by morphine and diazepam. Psychopharmacology (Berl) 1992;108:147-52.  Back to cited text no. 12
Lee MH, Kim H, Kim SS, Lee TH, Lim BV, Chang HK, et al. Treadmill exercise suppresses ischemia-induced increment in apoptosis and cell proliferation in hippocampal dentate gyrus of gerbils. Life Sci 2003;73:2455-65.  Back to cited text no. 13
Sim YJ, Kim SS, Kim JY, Shin MS, Kim CJ. Treadmill exercise improves short-term memory by suppressing ischemia-induced apoptosis of neuronal cells in gerbils. Neurosci Lett 2004;372:256-61.  Back to cited text no. 14
Kim SH, Kim HB, Jang MH, Lim BV, Kim YJ, Kim YP, et al. Treadmill exercise increases cell proliferation without altering of apoptosis in dentate gyrus of Sprague-Dawley rats. Life Sci 2002;71:1331-40.  Back to cited text no. 15
Yosefi M, Reisi P, Alaei H, Pilehvarian AA, Rashidi B. Treadmill running improves spatial learning and memory in the rats with intracerebroventricular injection of streptozotocin. J Res Med Sci 2011;16:1386-7.  Back to cited text no. 16
[PUBMED]  Medknow Journal  
Reisi P, Alaei H, Babri S, Sharifi MR, Mohaddes G. Effects of treadmill running on spatial learning and memory in streptozotocin-induced diabetic rats. Neurosci Lett 2009;455:79-83.  Back to cited text no. 17
Asl NA, Sheikhzade F, Torchi M, Roshangar L, Khamnei S. Long-term regular exercise promotes memory and learning in young but not in older rats. Pathophysiology 2008;15:9-12.  Back to cited text no. 18
Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: Key roles of growth factor cascades and inflammation. Trends Neurosci 2007;30:464-72.  Back to cited text no. 19
Arida RM, Scorza CA, da Silva AV, Scorza FA, Cavalheiro EA. Differential effects of spontaneous versus forced exercise in rats on the staining of parvalbumin-positive neurons in the hippocampal formation. Neurosci Lett 2004;364:135-8.  Back to cited text no. 20
Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF. Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 2001;25:729-41.  Back to cited text no. 21
Parikh D, Hamid A, Friedman TC, Nguyen K, Tseng A, Marquez P, et al. Stress-induced analgesia and endogenous opioid peptides: The importance of stress duration. Eur J Pharmacol 2011;650:563-7.  Back to cited text no. 22
Binder W, Mousa SA, Sitte N, Kaiser M, Stein C, Schäfer M. Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue. Eur J Neurosci 2004;20:92-100.  Back to cited text no. 23
Markowitz R, Jacobson J, Bain G, Kornetsky C. Naloxone blockade of morphine analgesia: A dose-effect study of duration and magnitude. J Pharmacol Exp Ther 1976;199:385-8.  Back to cited text no. 24
Hamidi G, Arabpour Z, Shabrang M, Rashidi B, Alaei H, Sharifi MR, et al. Erythropoietin improves spatial learning and memory in streptozotocin model of dementia. Pathophysiology 2013;20:153-8.  Back to cited text no. 25
Kramer AF, Hahn S, Cohen NJ, Banich MT, McAuley E, Harrison CR, et al. Ageing, fitness and neurocognitive function. Nature 1999;400:418-9.  Back to cited text no. 26
Van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A 1999;96:13427-31.  Back to cited text no. 27
Sutoo D, Akiyama K. Regulation of brain function by exercise. Neurobiol Dis 2003;13:1-14.  Back to cited text no. 28
Barnes CA, Forster MJ, Fleshner M, Ahanotu EN, Laudenslager ML, Mazzeo RS, et al. Exercise does not modify spatial memory, brain autoimmunity, or antibody response in aged F-344 rats. Neurobiol Aging 19910;12:47-53.  Back to cited text no. 29
Duclos M, Martin C, Malgat M, Mazat JP, Chaouloff F, Mormède P, et al. Relationships between muscle mitochondrial metabolism and stress-induced corticosterone variations in rats. Pflugers Arch 2001;443:218-26.  Back to cited text no. 30
Eichenbaum H, Otto T, Cohen NJ. The hippocampus – What does it do? Behav Neural Biol 1992;57:2-36.  Back to cited text no. 31
Lynch MA. Long-term potentiation and memory. Physiol Rev 2004;84:87-136.  Back to cited text no. 32
Sapolsky R. Stress, the Aging Brain and the Mechanisms of Neuron Death. Cambridge, MA: MIT Press; 1992.  Back to cited text no. 33
Tanapat P, Hastings NB, Rydel TA, Galea LA, Gould E. Exposure o fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J Comp Neurol. 2001;437 (4):496-504.  Back to cited text no. 34
Gould E, Tanapat P, McEwen BS, Flügge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A 1998;95:3168-71.  Back to cited text no. 35
McEwen BS, de Leon MJ, Lupien SJ, Meaney MJ. Corticosteroids, the Aging Brain and Cognition. Trends Endocrinol Metab 1999;10:92-96.  Back to cited text no. 36
McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol 1995;5:205-16.  Back to cited text no. 37
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.  Back to cited text no. 38
Wyss JM, Chambless BD, Kadish I, van Groen T. Age-related decline in water maze learning and memory in rats: Strain differences. Neurobiol Aging 2000;21:671-81.  Back to cited text no. 39
Farhadinasab A, Shahidi S, Najafi A, Komaki A. Role of naloxone as an exogenous opioid receptor antagonist in spatial learning and memory of female rats during the estrous cycle. Brain Res 2009;1257:65-74.  Back to cited text no. 40
Cohen RM, Cohen MR, Weingartner H, Pickar D, Murphy DL. High-dose naloxone affects task performance in normal subjects. Psychiatry Res 1983;8:127-36.  Back to cited text no. 41
Laukkanen V, Kärkkäinen O, Kautiainen H, Tiihonen J, Storvik M. Decreased [3H]naloxone binding in the dentate gyrus of cloninger type 1 anxiety-prone alcoholics: A postmortem whole-hemisphere autoradiography study. Alcohol Clin Exp Res 2015;39:1352-9.  Back to cited text no. 42
Su CF, Chang YY, Pai HH, Liu IM, Lo CY, Cheng JT. Mediation of beta-endorphin in exercise-induced improvement in insulin resistance in obese Zucker rats. Diabetes Metab Res Rev 2005;21:175-82.  Back to cited text no. 43
Shiigi Y, Takahashi M, Kaneto H. Facilitation of memory retrieval by pretest morphine mediated by mu but not delta and kappa opioid receptors. Psychopharmacology (Berl) 1990;102:329-32.  Back to cited text no. 44
Good AJ, Westbrook RF. Effects of a microinjection of morphine into the amygdala on the acquisition and expression of conditioned fear and hypoalgesia in rats. Behav Neurosci 1995;109:631-41.  Back to cited text no. 45
Madden J 4th, Akil H, Patrick RL, Barchas JD. Stress-induced parallel changes in central opioid levels and pain responsiveness in the rat. Nature 1977;265:358-60.  Back to cited text no. 46