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17 Journal of Clinical Sport Psychology, 2008, 2, 17-24 © 2008 Human Kinetics, Inc. Exercise Dependence and Morphine Addiction: Evidence From Animal Models Anthony Ferreira, Fabien Cornilleau, Fernando Perez-Diaz, and Charles Cohen-Salmon CNRS Laboratory Pitié Salpêtrière Hospital, Paris This study used animal models to examine potential similarities between depen- dence on physical activity (i.e., exercise) and dependence on morphine. Using C57BL/6 mice, the study also tested the hypothesis that physical exercise (e.g., long-term wheel running) may enhance vulnerability to the development of mor- phine dependence. The existence of an endorphin-related dependence induced by physical activity was also assessed. Naloxone was used to precipitate morphine withdrawal in mice accustomed to morphine. Specifically, the study sought to assess the intensity of addiction provoked by injection of morphine in mice that engaged in wheel-running activity as opposed to inactive mice. After 25 days of free access to activity wheel, mice that engaged in wheel-running demonstrated increased vulnerability to naloxone-induced withdrawal symptoms, which may be linked to activation of peripheral, as opposed to central, opioid receptors. These results indicate a behavioral interaction in which engaging in wheel running appears to potentiate the effects of morphine addiction. Implications of these findings for understanding human behavior and exercise addiction are also discussed. Keywords: addiction, exercise, behavioral dependence, morphine, physical activity Despite the general opinion that exercise and sport are good for health, it has been shown that intensive physical activity in humans can lead not only to an addiction to such activity (Hausenblas & Symons Downs, 2002) but also increased vulnerability to substance abuse, including use of psychostimulants and opiates (Nativ, Puffer, & Green, 1997; O’Brien & Lyons, 2000; Rainey, McKeown, Sar- gent, & Valois, 1996; Schwenk, 2000; Scully, Kremer, Meade, Graham, & Dud- geon, 1998; Thombs, 2000; Tricker, 2000). In animals, it has been shown that a dependence on physical activity can occur and that this dependence can foster the development of other addictions through sensitization of dopaminergic pathways (Ferreira et al., 2006). In humans, the neurobiological substrate of physical-activity dependence has not been clearly identified. While researchers appear to have found increases in the Anthony Ferreira is now with Unité des Yersinia Institut Pasteur, Paris. e-mail: [email protected]. Fabien Cornilleaus, Fernando Perez-Diaz, and Charles Cohen-Salmon are with CNRS UMR 7593 Pitié Salpêtrière Hospital, Paris.

Exercise Dependence and Morphine Addiction: Evidence …€¦ · Exercise Dependence and Morphine Addiction: ... O’Brien & Lyons, 2000; Rainey, McKeown, Sar-gent, & Valois, 1996

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Journal of Clinical Sport Psychology, 2008, 2, 17-24 © 2008 Human Kinetics, Inc.

Exercise Dependence and Morphine Addiction: Evidence From Animal Models

Anthony Ferreira, Fabien Cornilleau, Fernando Perez-Diaz, and Charles Cohen-Salmon

CNRS Laboratory Pitié Salpêtrière Hospital, Paris

This study used animal models to examine potential similarities between depen-dence on physical activity (i.e., exercise) and dependence on morphine. Using C57BL/6 mice, the study also tested the hypothesis that physical exercise (e.g., long-term wheel running) may enhance vulnerability to the development of mor-phine dependence. The existence of an endorphin-related dependence induced by physical activity was also assessed. Naloxone was used to precipitate morphine withdrawal in mice accustomed to morphine. Specifically, the study sought to assess the intensity of addiction provoked by injection of morphine in mice that engaged in wheel-running activity as opposed to inactive mice. After 25 days of free access to activity wheel, mice that engaged in wheel-running demonstrated increased vulnerability to naloxone-induced withdrawal symptoms, which may be linked to activation of peripheral, as opposed to central, opioid receptors. These results indicate a behavioral interaction in which engaging in wheel running appears to potentiate the effects of morphine addiction. Implications of these findings for understanding human behavior and exercise addiction are also discussed.

Keywords: addiction, exercise, behavioral dependence, morphine, physical activity

Despite the general opinion that exercise and sport are good for health, it has been shown that intensive physical activity in humans can lead not only to an addiction to such activity (Hausenblas & Symons Downs, 2002) but also increased vulnerability to substance abuse, including use of psychostimulants and opiates (Nativ, Puffer, & Green, 1997; O’Brien & Lyons, 2000; Rainey, McKeown, Sar-gent, & Valois, 1996; Schwenk, 2000; Scully, Kremer, Meade, Graham, & Dud-geon, 1998; Thombs, 2000; Tricker, 2000). In animals, it has been shown that a dependence on physical activity can occur and that this dependence can foster the development of other addictions through sensitization of dopaminergic pathways (Ferreira et al., 2006).

In humans, the neurobiological substrate of physical-activity dependence has not been clearly identified. While researchers appear to have found increases in the

Anthony Ferreira is now with Unité des Yersinia Institut Pasteur, Paris. e-mail: [email protected]. Fabien Cornilleaus, Fernando Perez-Diaz, and Charles Cohen-Salmon are with CNRS UMR 7593 Pitié Salpêtrière Hospital, Paris.

18 Ferreira et al.

circulating levels of β-endorphin during physical exercise (Goldfarb & Jamurtas, 1997; Sforzo, Seeger, Pert, Pert, & Dotson, 1986), the role that this neurotransmit-ter activity might play in the “runner’s high” reported by athletes (e.g., marathon runners) is not at all clear (Janal, Colt, Clark, & Glusman, 1984; Maas et al., 1998; Markoff, Ryan, & Young, 1982; Sforzo et al., 1986; Wildmann, Kruger, Schmole, Niemann, & Matthaei, 1986). The runner’s high experience, which has also been known as the “second wind,” refers to feelings of euphoria and power reported during and after a race. It has been described as an altered state of consciousness, an experience of dissociation between the mind and body in which the body appears to perform the activity very easily while the mind that floats above it in a “trance-like” state (Masters, 1992; Wagemaker & Goldstein, 1980). More often than not, researchers have conceptualized runner’s high as the effect of a neurobiological mechanism and have suggested that it is this same mechanism that accounts for the phenomenon of exercise addiction (Pierce, 1994; Pierce, Eastman, Tripathi, Olson, & Dewey, 1993).

PurposeUsing an animal model of behavioral dependence on physical activity (Ferreira et al., 2006) and naloxone to precipitate morphine withdrawal in animals accustomed to morphine, this study attempted to verify the hypothesis that physical activity may enhance vulnerability to the development of morphine dependence. Findings of this study are, of course, specific to the framework of an animal model and, therefore, removed from any psychosocial considerations related to exercise in humans. Nevertheless, they offer information that could enhance understanding of the underlying physiological processes contributing to exercise addiction.

The protocol used in this study, which was adapted from a protocol employed by Noda, Mamiya, and Nabeshima (2001), induced a real morphine dependence in the animal subjects, albeit one of relatively low intensity compared with some other protocols that use morphine in much higher doses. Naloxone, an opioid antagonist, was then administered to precipitate withdrawal symptoms, which could then be observed and counted. The model assumes that addiction can be understood in terms of the number, rather than the intensity, of morphine with-drawal symptoms precipitated by administration of naloxone (Kest et al., 2002). The principle of investigation is to compare the number of withdrawal symptoms naloxone administration precipitates in the experimental group to the number it engenders in a control group. In this case, the experimental condition involved access to physical activity (i.e., wheel running), while the control condition allowed no access to this activity.

In addition to revealing the effects of activity on morphine withdrawal, the experimental model also provides information regarding the existence of endorphin-related dependence. Since naloxone also blocks the action of endorphins, which also rely on opioid receptor systems, it can be used to highlight potential withdrawal effects in animals that engage in chronic physical activity but receive no access to morphine. For this portion of the study, neither the group permitted to exercise nor the no-exercise control group received access to morphine, but both are assessed for presence of withdrawal symptoms following injection of naloxone. If exercise addiction is, in fact, related to endorphin-dependence, the naloxone administration

Exercise Dependence and Morphine Addiction    19

should precipitate withdrawal symptoms in animals permitted to exercise in the same manner that it does for animals dependent on morphine.

Thus, the hypotheses for this study were twofold:

1. Morphine-dependent animals with regular access to physical activity will display a greater number of withdrawal symptoms following naloxone administration than will morphine-dependent animals that are chronically deprived of physical activity.

2. Non-morphine-dependent animals allowed regular access to physical activity will display a greater number of withdrawal symptoms following naloxone administration than will non-morphine-dependent animals that are chronically deprived of access to physical activity.

Method

Animals

Twenty 8-week-old male C57BL/6 (Iffa-Credo, France) mice were used in the study. The animals were housed individually in an animal supply facility (12-hr light/dark cycle, from 7:00 a.m. to 7:00 p.m.; constant temperature 22 ± 1 °C) where they had ad libitum access to water and food. All experiments were carried out in accordance with the Declaration of Helsinki and with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health and the European Union.

Groups and Treatment

The study required creation of four groups: (a) a morphine-dependent group with access to a running wheel, (b) a morphine-dependent group with no access to a running wheel, (c) a nonmorphine dependent group with access to a running wheel, and (d) a non-morphine-dependent group with no access to a running wheel. For the morphine-dependent condition, five mice in a control group without access to a running wheel and five in a group with continuous free access to a running wheel were treated with morphine at 10 mg/kg i.p. twice a day for four consecu-tive days with one treatment on the fifth day. After the last morphine injection, withdrawal was precipitated with a single injection of naloxone (5 mg/kg i.p.). Withdrawal signs were observed and recorded for a period of 15 minutes. For the non-morphine-dependent condition, five mice in a control group with no access to a running wheel and five in a group with continuous free access to a running wheel received an equal volume of saline solution instead of morphine. After the last injection, withdrawal was precipitated with a single injection of naloxone (5 mg/kg i.p.). Again, withdrawal signs were observed and recorded for a period of 15 minutes. During treatment, animals stayed in their housing cage (with or without wheel according to treatment condition).

Measurement

The measurement protocol was adapted from a previous study on animal models of physical activity dependence (Ferreira et al., 2006): ten mice, five

20 Ferreira et al.

morphine-dependent and five non-morphine-dependent, had continuous free access to a running wheel. To ensure that the animals in the active groups did, in fact, engage in exercise, the running wheels were equipped with detectors linked to a computer system (provided by Intellibio), which recorded the number of revolutions and the amount of activity over time. In addition, 10 mice (5 morphine-dependent and 5 nonmorphine dependent) were individually housed in cages without access to a running wheel. All animals were housed in their cages for 3 weeks (21 days) before the morphine protocol was initiated, so that they could acclimate to their surroundings and become accustomed to engaging in wheel-running activity.

During observation of withdrawal symptoms, mice were placed in Perspex boxes (20 × 15 × 30 cm) with bedding and were video-recorded. Jumps and burrow-ing behaviors induced by naloxone (5 mg/kg i.p.) during the first 15 min following administration were observed and recorded.

Statistics

Data were expressed as the mean ± SE of measurement (S.E.M.). The statistical significance of differences was evaluated by analysis of variance (ANOVA) and the Bonferroni post hoc test (p < 0.05 was considered significant).

ResultsFollowing naloxone administration, both the morphine-dependent groups (active group and inactive control group) demonstrated a significant increase in the number of jumps. In the active groups, morphine-dependent mice averaged 12.8 ± 3.05 jumps, compared with 0.2 ± 0.2 jumps for the group receiving saline, F(1,8) = 16.93, p = 0.003. In the inactive control groups, morphine-dependent mice aver-aged 3.8 ± 0.37 jumps, while the group receiving saline averaged 0 ± 0 jumps. F(1,8) = 103.14, p < 0.001 (see Figure 1). In addition, the number of jumps was higher in the morphine-dependent active group than in the morphine-dependent inactive group, F(1,8) = 8.54, p = 0.02, while there was no difference between the two non-morphine-dependent groups, F(1,8) = 1.0, ns (see Figure 1).

The amount of burrowing activity following naloxone administration was greater in the inactive morphine-dependent group than in the inactive nonmorphine dependent group, but there were no differences in burrowing activity between the active morphine-dependent and active non-morphine-dependent groups. The mean number of burrowing attempts for active morphine-dependent mice was 41.6 ± 5.71, while the mean number for active nonmorphine dependent mice was 29.8 ± 4.58, F(1,8) = 2.59, ns. The difference in burrowing attempts was significant, however, between the inactive morphine-dependent and inactive non-morphine-dependent groups. Inactive morphine-dependent mice averaged 17.2 ± 1.82 burrowing attempts, while inactive non-morphine-dependent mice averaged 10 ± 1.78 attempts, F(1,8) = 7.93, p = 0.02 (see Figure 2). In addition, among morphine-dependent mice, the amount of burrowing activity was higher in the active group than in the inactive control group, F(1,8) = 16.54, p = 0.004; and among non-morphine-depen-dent mice, the active group engaged in more burrowing attempts than the inactive group, F(1,8) = 16.17, p = 0.004 (see Figure 2).

Exercise Dependence and Morphine Addiction    21

Figure 1 — Number of jumps precipitated by naloxone in morphine-dependent and non-morphine-dependent (saline administration) mice in both active groups and inactive con-trols. Data include mean number of jumps ± SEM for each group. Naloxone administration precipitated more jumps in the morphine-dependent active group (12.8 ± 3.05) than in the non-morphine-dependent active group (0.2 ± 0.2), F(1, 8) = 16.93, p = 0.003. Similarly, naloxone administration precipitated more jumps in morphine-dependent animals (3.8 ± 0.37) than in non-morphine-dependent animals (0 ± 0), F(1, 8) = 103.14, p < 0.001. Nal-oxone administration also yielded a higher number of jumps in the morphine-dependent active group than in the morphine dependent inactive group F(1, 8) = 8.54, p = 0.02, but this difference was not found between the non-morphine-dependent active and inactive groups, F(1, 8) = 1.00, p = 0.35. (*p < 0.05; ***p < 0.0001).

DiscussionMorphine pretreatment successfully induced dependence in the treatment groups, and naloxone administration resulted in precipitation of withdrawal symptoms. As expected, inactive morphine-dependent animals exhibited significantly more withdrawal behaviors (i.e., jumps and burrowing efforts) than inactive animals that were not morphine-dependent. Moreover, in keeping with the first hypothesis, morphine-dependent animals with access to physical activity displayed a greater number of withdrawal symptoms following naloxone administration than did morphine-dependent animals without access to physical activity. It is reasonable to conclude from these findings that chronic engagement in wheel-running activity increased the intensity of the morphine dependency and exacerbated the withdrawal effects elicited by administration of naloxone.

The study’s second hypothesis, however, was only partially confirmed. Mice in the active non-morphine-dependent group showed no difference from animals

22 Ferreira et al.

in the inactive non-morphine-dependent group in the number of jumps following naloxone administration, though they did engage in more burrowing activity. In fact, burrowing occurred at the same rate in active non-morphine-dependent animals as it did in active morphine-dependent animals. In other words, activity alone allowed for precipitation of this withdrawal symptom. One likely explanation for this phenomenon is that morphine- and exercise-related endorphin activity involve multiple opioid receptor systems and the two withdrawal symptoms measured here (jumps and burrowing) reflect withdrawal effects relating to these different systems. Specifically, burrowing efforts have been associated with peripheral opiate receptors, while jumping has been linked to central opiate receptors (Sharif & el-Kadi, 1996). Naloxone blocks all opiate receptors—central and peripheral—so it should precipitate withdrawal symptoms for either system that is involved. Interestingly, of the active groups, only the morphine-dependent mice exhibited jumps following naloxone administration, but both morphine-dependent and nonmorphine dependent mice exhibited increased burrowing activity. This difference was not observed in the inactive groups, where only morphine-dependent mice demonstrated withdrawal symptoms and the symptoms involved both jumps and burrowing efforts. The

Figure 2 — Number of jumps precipitated by naloxone in morphine-dependent and non-morphine-dependent (saline administration) mice in both active groups and inactive con-trols. Data include mean number of burrowing behaviors ± SEM for each group. Naloxone administration precipitated more burrowing behaviors in the morphine-dependent inactive control groups (17.2 ± 1.82) than in the non-morphine-dependent inactive group (10 ± 1.78), F(1, 8) = 7.93, p = 0.02. Naloxone administration did not precipitate a greater number of burrowing behaviors, however, in the morphine-dependent active group (41.6 ± 5.71) than in the non-morphine-dependent active group (29.8 ± 4.58), F(1, 8) = 2.5929, p = ns. Nalox-one administration did yield more burrowing behaviors in the morphine-dependent activity group than in the morphine-dependent inactive group, F(1, 8) = 16.53, p = 0.004, and more burrowing behaviors in the non-morphine-dependent active group than in the non-morphine-dependent inactive group, F(1, 8) = 16.17, p = 0.004. (*p < 0.05; **p < 0.01).

Exercise Dependence and Morphine Addiction    23

presence of withdrawal symptoms associated with peripheral receptors in animals that had access to physical activity but no morphine treatment suggests that exercise addiction (i.e., dependence on activity-related endorphin release) involves peripheral rather than central endorphin receptors.

In humans, exercise has been associated with an increase in circulating endor-phin levels in the blood stream (Goldfarb & Jamurtas, 1997; Sforzo et al., 1986). Because certain endorphins do not cross the blood-brain barrier (Sforzo, 1989), it is possible that circulating endorphins could trigger peripheral receptors without affecting central endorphin receptors. Opiates such as morphine, by contrast, affect both central and peripheral endorphin receptors so their withdrawal syndromes are associated with negative sensations, mood swings, and a general sense of illness. In other words, the endorphin receptors involved in exercise addiction do not appear to address receptors in the central nervous system (CNS). Given the absence of CNS involvement, the production of endorphins during exercise is likely to offer protection only from peripheral phenomena, such as pain or fatigue. Indeed, exer-cise-related endorphin release would not affect central reward symptoms and would not, therefore, serve as an etiological driver of increased appetence for exercise. Nevertheless, activity-related peripheral endorphin activity could be the underlying mechanism of the runner’s high phenomenon, and dependence on physical activity could develop as a result of the experience of this physiological event (i.e., pain relief, “second wind”), which would have strong reinforcing potential.

The mechanism by which activity increases potentiation of morphine depen-dence (as shown by significantly greater withdrawal symptoms exhibited in the active morphine-dependent animals) remains unclear. It could, however, result from the cross-sensitization of opioid receptor systems. Just as dependence on one substance tends to foster dependence on another, physical activity could increase sensitivity to morphine dependence. In fact, epidemiological studies have suggested a potential relationship between drug use and intense physical activity (Nativ et al., 1997; O’Brien & Lyons, 2000; Rainey et al., 1996; Schwenk, 2000; Scully et al., 1998; Thombs, 2000; Tricker, 2000). Drug use tends to increase during both periods of activity deprivation and periods of exercise, and athletes using poten-tially addictive substances, whether for doping or recreation, could be at greater risk of substance dependence than those who do not engage in intensive physical activity.

Because this study used animal models, its results have limited generaliz-ability. Nevertheless, these results point to underlying physiological mechanisms with significant implications for understanding both exercise addiction and athletes’ vulnerability to substance dependence. Given that ethical principles preclude use of addictive substances in human subjects research, the animal models used here offer a useful opportunity to understand the physiology of withdrawal in the context of physical activity.

ReferencesFerreira, A., Lamarque, S., Boyer, P., Perez-Diaz, F., Jouvent, R., & Cohen-Salmon, C.

(2006). Spontaneous appetence for wheel-running: A model of dependency on physical activity in rat. European Psychiatry, 21, 580–588.

Goldfarb, A.H., & Jamurtas, A.Z. (1997). Beta-endorphin response to exercise: An update. Sports Medicine (Auckland, N.Z.), 24, 8–16.

24 Ferreira et al.

Hausenblas, H.A., & Symons Downs, D. (2002). Exercise dependence: A systematic review. Psychology of Sport and Exercise, 3, 89–123.

Janal, M.N., Colt, E.W., Clark, W.C., & Glusman, M. (1984). Pain sensitivity, mood, and plasma endocrine levels in man following long-distance running: Effects of naloxone. Pain, 19, 13–25.

Kest, B., Palmese, C.A., Hopkins, E., Adler, M., Juni, A., & Mogil, J.S. (2002). Naloxone-precipitated withdrawal jumping in 11 inbred mouse strains: Evidence for common genetic mechanisms in acute and chronic morphine physical dependence. Neurosci-ence, 115, 463–469.

Maas, L.C., Lukas, S.E., Kaufman, M.J., Weiss, R.D., Daniels, S.L., Rogers, V.W., et al. (1998). Functional magnetic resonance imaging of human brain activation during cue-induced cocaine craving. The American Journal of Psychiatry, 155, 124–126.

Markoff, R.A., Ryan, P., & Young, T. (1982). Endorphins and mood changes in long-distance running. Medicine and Science in Sports and Exercise, 14, 11–15.

Masters, K.S. (1992). Hypnotic susceptibility, cognitive dissociation, and runner’s high in a sample of marathon runners. The American Journal of Clinical Hypnosis, 34, 193–201.

Nativ, A., Puffer, J.C., & Green, G.A. (1997). Lifestyle and health risks of collegiate athletes: A multi-center study. Clinical Journal of Sport Medicine, 7, 262–272.

Noda, Y., Mamiya, T., & Nabeshima, T. (2001). The mechanisms of morphine dependence and its withdrawal syndrome: Study in mutant mice. Nippon Yakurigaku Zasshi. Japa-nese Journal of Pharmacology, 117, 21–26.

O’Brien, C.P., & Lyons, F. (2000). Alcohol and the athlete. Sports Medicine (Auckland, N.Z.), 29, 295–300.

Pierce, E.F. (1994). Exercise dependence syndrome in runners. Sports Medicine (Auckland, N.Z.), 18, 149–155.

Pierce, E.F., Eastman, N.W., Tripathi, H.L., Olson, K.G., & Dewey, W.L. (1993). Beta-endor-phin response to endurance exercise: Relationship to exercise dependence. Perceptual and Motor Skills, 77, 767–770.

Rainey, C.J., McKeown, R.E., Sargent, R.G., & Valois, R.F. (1996). Patterns of tobacco and alcohol use among sedentary, exercising, nonathletic, and athletic youth. The Journal of School Health, 66, 27–32.

Schwenk, T.L. (2000). Alcohol use in adolescents: The scope of the problem and strategies for intervention. The Physician and Sportsmedicine, 28, 71–76.

Scully, D., Kremer, J., Meade, M.M., Graham, R., & Dudgeon, K. (1998). Physical exercise and psychological well-being: A critical review. British Journal of Sports Medicine, 32, 111–120.

Sforzo, G.A. (1989). Opioids and exercise: An update. Sports Medicine (Auckland, N.Z.), 7, 109–124.

Sforzo, G.A., Seeger, T.F., Pert, C.B., Pert, A., & Dotson, C.O. (1986). In vivo opioid recep-tor occupation in the rat brain following exercise. Medicine and Science in Sports and Exercise, 18, 380–384.

Sharif, S.I., & el-Kadi, A.O. (1996). The role of cholinergic systems in the expression of morphine withdrawal. Neuroscience Research, 25, 155–160.

Thombs, D.L. (2000). A test of the perceived norms model to explain drinking patterns among university student athletes. Journal of American College Health, 49, 75–83.

Tricker, R. (2000). Painkilling drugs in collegiate athletics: Knowledge, attitudes, and use of student athletes. Journal of Drug Education, 30, 313–324.

Wagemaker, H., & Goldstein, L. (1980). The runner’s high. The Journal of Sports Medicine and Physical Fitness, 20, 227–229.

Wildmann, J., Kruger, A., Schmole, M., Niemann, J., & Matthaei, H. (1986). Increase of circulating beta-endorphin-like immunoreactivity correlates with the change in feeling of pleasantness after running. Life Sciences, 38, 997–1003.