Voluntary and forced exercises prevent the development of tolerance to analgesic effects of morphine in rats

Document Type : Original Article


1 Department of Physiology, Islamic Azad University, Damghan Branch, Damghan, Iran

2 Laboratory of Animal Addiction Models Research Center and Department of Physiology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran

3 Islamic Azad University, Semnan Branch, Semnan, Iran


Objective(s):Morphine is widely used to treat chronic pain. However, its utility is hindered by the development of tolerance to its analgesic effects. Despite the renowned beneficial effects of physical exercise on cognitive functions and signs of morphine withdrawal in morphine-dependent rats, little is known about the roles of voluntary and forced exercises in tolerance to analgesic effect of morphine in rats.
Materials and Methods: In this study, rats were injected with 10 mg/kg of morphine, once daily, SC over a period of 8 days of either voluntary or treadmill exercise. Following these injections, the percent of maximum possible effect (%MPE) of morphine was measured on the 1st, 4th, and 8th days by hot plate test.
Results: Both voluntary and forced exercises significantly increased pain threshold compared to the sedentary group (P<0.05). Voluntary and forced exercises also significantly increased potency of morphine compared to sedentary morphine group (P<0.05). Thus, we concluded that voluntary and forced exercises blocked the development of tolerance during 8 daily simultaneously treatments. When exercising rats were returned to sedentary conditions, sensitivity to the analgesic effects of morphine increased significantly and persisted during sedentary period in the exercising rats. In other words, %MPE of the exercising morphine-group increased significantly compared to saline group (P<0.05).
Conclusion: Our results showed that voluntary and forced exercises may be possible methods for treating the development of tolerance to analgesic effect of morphine in rats.


1. Koob GF, LeMoal M. Drug abuse: hedonic homeostatic dysregulation. Science 1997; 278:52–58.
2. Nestler EJ, Aghajanian GK. Molecular and cellular basis of addiction. Science 1997; 278:58-63.
 3.  Rawls SM, Zielinski M, Patel H, Sacavage S, Baron DA, Patel D. Beta-lactam antibiotic reduces morphine analgesic tolerance in rats through GLT-1 transporter activation. Drug Alcohol Depend 2010; 107:261-263.
4.  Ko SW, Wu LJ, Shum F, Quan J, Zhuo M. Cingulate NMDA NR2B receptor contribute to morphine-induced analgesic tolerance. Mol Brain 2008; 1:2.
5. Gudehithlu KP, Tejwani GA, Bhargava HN. Beta-endorphin and methionine-enkephalin levels in discrete brain regions, spinal cord, pituitary gland and plasma of morphine tolerant-dependent and abstinent rats. Brain Res 1991; 553:284-290.
6. Rattan AK, Koo KL, Tejwani GA, Bhargava HN. The effect of morphine tolerance dependence and abstinence on immunoreactive dynorphin (1-13) levels in discrete brain regions, spinal cord, pituitary gland and peripheral tissues of the rat. Brain Res 1992; 584:207-212.
7. Wan XW, Li WH, Huang M, You ZD, Tan YX, Lu CL, et al. Levels of immunoreactive dynorphin A1-13 during development of morphine dependence in rats. Zhongguo Yao Li Xue Bao 1998; 19:560-563.
8.  Janal MN. Pain sensitivity, exercise and stoicism. J R Soc Med 1996; 89:376-381.
9.  O'Connor PJ, Cook DB. Exercise and pain: the neurobiology, measurement, and laboratory study of pain in relation to exercise in humans. Exerc Sport Sci Rev 1999; 27:119-166.
10.  Koltyn KF. Analgesia following exercise: a review. Sports Med 2000; 29:85-98.
11.  Kim DH, Ko IG, Kim BK, Kim TW, Kim SE, Shin MS, et al. Treadmill exercise inhibits traumatic brain injury-induced hippocampal apoptosis. Physiol Behav 2010; 101:660-665.
12. Stagg NJ, Mata HP, Ibrahim MM, Henriksen EJ, Porreca F, Vanderah TW, et al. Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids. Anesthesiology 2011; 114:940-948.
13.  Mazzardo-Martins L, Martins DF, Marcon R, Dos Santos UD, Speckhann B, Gadotti VM, et al. High-intensity extended swimming exercise reduces pain-related behavior in mice: involvement of endogenous opioids and the serotonergic system. J Pain 2010; 11:1384-1393.
14.  Galdino GS, Duarte ID, Perez AC. Participation of endogenous opioids in the antinociception induced by resistance exercise in rats. Braz J Med Biol Res 2010; 43:906-909.
15. McLachlan CD, Hay M, Coleman GJ. The effects of exercise on the oral consumption of morphine and methadone in rats. Pharmacol Biochem Behav 1994; 48:563-658.
16.  Miladi-Gorji H, Rashidy-Pour A, Fathollahi Y, Akhavan MM, Semnanian S, Safari M. Voluntary exercise ameliorates cognitive deficits in morphine dependent rats: the role of hippocampal brain-derived neurotrophic factor. Neurobiol Learn Mem 2011; 96:479-491.
17.  Miladi-Gorji H, Rashidy-Pour A, Fathollahi Y. Anxiety profile in morphine-dependent and withdrawn rats: effect of voluntary exercise. Physiol Behav 2012; 105:195-202.
18. Smith MA, Lyle MA. Chronic exercise decreases sensitivity to mu opioids in female rats: correlation with exercise output. Pharmacol Biochem Behav 2006; 85:12-22.
19.  Smith MA, Yancey DL. Sensitivity to the effects of opioids in rats with free access to exercise wheels: mu-opioid tolerance and physical dependence. Psychopharmacology 2003; 168:426-434.
20.  Lett BT, Grant VL, Koh MT, Flynn G. Prior experience with wheel running produces cross-tolerance to the rewarding effect of morphine. Pharmacol Biochem Behav 2002; 72:101-105.
21. Cotman CW, Engesser-Cesar C. Exercise enhances and protects brain function. Exerc Sport Sci Rev 2002; 30:75-79.
22. Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 2004; 20:2580- 2590.
23.  Kuphal KE, Fibuch EE, Taylor BK. Extended swimming exercise reduces inflammatory and peripheral neuropathic pain in rodents. J Pain 2007; 8:989-997.
24. Hoffmann P, Skarphedinsson JO, Delle M, Thorén P. Electrical stimulation of the gastrocnemius muscle in the spontaneously hypertensive rat increases the pain threshold: role of different serotonergic receptors. Acta Physiol Scand 1990; 138:125-131.
25.  Shyu BC, Andersson SA, Thorén P. Endorphin mediated increase in pain threshold induced by long-lasting exercise in rats. Life Sci 1982; 30:833-840.
26.  Mathes WF, Kanarek RB. Chronic running wheel activity attenuates the antinociceptive actions of morphine and morphine-6-glucouronide administration into the periaqueductal gray in rats. Pharmacol Biochem Behav 2006; 83:578-584.
27. Hutchinson KJ, Gómez-Pinilla F, Crowe MJ, Ying Z, Basso DM. Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats. Brain 2004; 127:1403-1414.
28. Cobianchi S, Marinelli S, Florenzano F, Pavone F, Luvisetto S. Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury. Neuroscience 2010; 168:273-287.
29. Bement MK, Sluka KA. Low-intensity exercise reverses chronic muscle pain in the rat in a naloxone-dependent manner. Arch Phys Med Rehabil 2005; 86:1736-1740.
30. Aravich PF, Rieg TS, Lauterio TJ, Doerries LE. Beta-endorphin and dynorphin abnormalities in rats subjected to exercise and restricted feeding: relationship to anorexia nervosa? Brain Res 1993; 622:1-8.
31. Hoffmann P, Terenius L, Thorén P.  Cerebrospinal fluid immunoreactive beta-endorphin concentration is increased by voluntary exercise in the spontaneously hypertensive rat. Regul Pept 1990; 28:233-239.
32. 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, 21:175-182.
33. Galdino GS, Cortes SF, Duarte ID, Perez AC. Involvement of the nitric oxide/(C)GMP/K(ATP) pathway in antinociception induced by exercise in rats. Life Sci 2010; 86:505-509.
34. Perez AC, de Oliveira CC, Prieto JG, Ferrando A, Vila L, Alvarez AI. Quantitative assessment of nitric oxide in rat skeletal muscle and plasma after exercise. Eur J Appl Physiol 2002; 88:189-191.
35. Diaz A, Ruiz F, Florez J, Hurle MA, Pazos A.  Mu-opioid receptor regulation during opioid tolerance and supersensitivity in rat central nervous system. J Pharmacol Exp Ther 1995; 274:1545–1551.
36. Sarkaki AR, Saadipour KH, Badavi M, Alaei H, Rahim F. Effects of forced treadmill exercise on pain threshold in morphine-addicted rats. J Clin Diagn Res 2007; 1:555-560.
37. Hosseini M, Alaei HA, Naderi A, Sharifi MR, Zahed R. Treadmill exercise reduces self-administration of morphine in male rats. Pathophysiology 2009; 16:3-7.
38. Nawa H, Pelleymounter MA, Carnahan J. Intraventricular administration of BDNF increases neuropeptide expression in newborn rat brain. J Neurosci 1994; 14:3751-3765.
39.  Siuciak JA, Wong V, Pearsall D, Wiegand SJ, Lindsay RM. BDNF produces analgesia in the formalin test and modifies neuropeptide levels in rat brain and spinal cord areas associated with nociception. Eur J Neurosci 1995; 7:663-670.
40. Siuciak JA, Altar CA, Wiegand SJ, Lindsay RM. Antinociceptive effect of brain-derived neurotrophic factor and neurotrophin-3. Brain Res. 1994; 633:326-330.
41. Golland LC, Evans DL, Stone GM, Tyler-McGowan CM, Hodgson DR, Rose RJ. Maximal exercise transiently disrupts hormonal secretory patterns in standard bred geldings. Equine Vet J Suppl 1999; 30:581–585.