Mental Health and Physical Activity 2 (2009) 4–9
Contents lists available at ScienceDirect
Mental Health and Physical Activity
journal homepage: www.elsevier.com/locate/menpa
Lessons in exercise neurobiology: The case of endorphins
Rod K. Dishman*, Patrick J. O’Connor
Department of Kinesiology, Biomedical Health Sciences Institute, Neuroscience Section, The University of Georgia, Athens, Georgia, USA
article info abstract
Article history: This paper focuses on application of neuroscience techniques to exercise psychology for the purpose of
Received 20 January 2009 obtaining better answers to questions about the effects of acute exercise on mood and other affective
Accepted 20 January 2009 experiences. We do this through the lens of the popular idea that exercise can cause an endorphin-based
high. Endogenous opioids and their interaction with other neurotransmitter systems are discussed,
Keywords: followed by a succinct historical account of the effects of acute exercise on endorphins and mood.
Limitations of the approaches that have been taken are identiﬁed. A key message is that optimal progress
toward truly understanding the psychological consequences of exercise will require that neuroscience
Central nervous system
techniques be combined with the strongest possible research designs.
Ó 2009 Elsevier Ltd. All rights reserved.
There is sufﬁcient evidence to conclude that regular participa- prolonged exercise (Boecker, Sprenger, et al., 2008). This ﬁnding
tion in moderate-to-vigorous physical activity is associated with represents a signiﬁcant advance for exercise neuroscience and it
several positive aspects of mental health (Warburton, Katzmarzyk, could help move this research area forward by promoting acceler-
Rhodes, & Shephard, 2007; http://www.health.gov/PAGuidelines/ ated application of clinical neuroscience methods to the study of
Report/G8_mentalhealth.aspx). Nonetheless, it remains prema- human exercise, which has been infrequent (Dishman, 2005;
ture to conclude that physical activity causes these positive aspects Dishman et al., 2006).
of mental health (De Moor, Boomsma, Stubbe, Willemsen, & de Shortcomings of the Boecker brain imaging study also are
Geus, 2008; Morgan, 1997). This lack of surety results in part from instructive for guiding future research aimed at discovering
our poor understanding of how acute or chronic physical activity whether neurobiological responses and adaptations to exercise are
affect the central nervous system. Advances in our understanding convincingly linked to changes in affect, behavior or cognition. To
will not occur without acceleration in the number and quality of illustrate, we will consider whether the observations of high
studies that apply neuroscience to the controlled study of brain and correlations (>0.70) between self-ratings of euphoria and opioid
behavior in physical activity settings. Especially needed are studies binding in frontolimbic brain regions strongly support the idea that
that synergize human brain imaging with behavioral neuroscience the endogenous opioid system plays a speciﬁc role in the ‘‘runner’s
approaches that use animal models of human function or disease high’’ phenomenon (Boecker, Sprenger, et al., 2008). It will be
(e.g., Dishman, 1997; Dishman et al., 2006; Holmes, 2003). Appli- useful to ﬁrst provide background information about endogenous
cation of neuroscience to exercise psychology is necessary to opioids and their interaction with other neurotransmitter systems,
eliminate and elucidate plausible neurobiological mechanisms and as well as a brief historical account of the effects of acute exercise
thereby enhance our understanding of whether physical activity on endorphins and mood. We focus on mood here because most of
truly beneﬁts mental health (Boecker, Henriksen, et al., 2008; the relevant literature has used mood measures. Elsewhere we
Dishman, 2005; Meeusen, Piacentini, & De Meirleir, 2001). have emphasized the potential usefulness of measuring other
The promise of applying neuroscience to exercise psychology aspects of affective experience (Crabbe, Smith, & Dishman, 2007;
questions is illustrated in a recent, headline grabbing brain imaging Smith & O’Connor, 2003).
study (http://en.wikipedia.org/wiki/Endorphin; Boecker, 2008).
The investigation, which measured brain opioid binding using
1. Endogenous opioids
positron emission tomography (PET), provided the ﬁrst evidence
that endogenous opioids are released in human brains after
Endogenous opioids (endorphins, enkephalins, and dynorphins)
are peptides that have biochemical properties similar to exogenous
opiates such as heroin and morphine. Endogenous opioids act by
* Corresponding author. Ramsey Center, 330 River Road, Athens, Georgia 30602-
binding to mu, kappa or delta receptors. Because of the widespread
6554, USA. Tel.: þ1 706 542 9840; fax: þ1 706 542 3148.
distribution of these receptors throughout the peripheral nervous
E-mail address: email@example.com (R.K. Dishman).
1755-2966/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
R.K. Dishman, P.J. O’Connor / Mental Health and Physical Activity 2 (2009) 4–9 5
system, spinal cord and brain, endogenous opioids have diverse example, a large body of research suggests that dopamine signaling
effects including involvement in addiction, pain regulation, cardio- plays a role in euphoric states, such as those induced by cocaine and
vascular regulation, respiration, appetite and thirst, gastrointestinal other psychoactive drugs. Little is known about the effects of
activity, renal function, temperature regulation, metabolism, physical activity on the brain meso-limbic dopamine (DA) system
hormonal secretion, reproduction, immunity, learning, and memory (mainly the neural circuit between the VTA, the nucleus accumbens
(Evans, Hammond, & Frederickson, 1988). Met-enkephalin and leu- of the ventral striatum, and the frontal cortex). This system plays
enkephalin are also stored in the adrenal medulla where they are co- a key role in the regulation of hedonics and motivated behavior
released with catecholamines into the gastrointestinal tract, heart, (including addiction) and is modulated by brain opioids. Treadmill
and blood circulation during stress. Endomorphins, more recently running acutely increases DA release (Meeusen et al., 2001) and
discovered endogenous substances with a different structure than turnover (Hattori, Naoi, & Nishino, 1994) and chronically up-regu-
opioids, bind more tightly to the mu receptor than endorphins and lates D2 receptors (MacRae, Spirduso, Walters, Farrar, & Wilcox,
also have wide ranging effects, many of which mimic the effects of 1987) in the striatum of rats, but forced treadmill running by rats
opioids (Fichna, Janecka, Costentin, & DoRego, 2007). and mice likely confounds exertion with emotional stress and is thus
Investigators studying opioids and exercise have focused most of a poor model of voluntary physical activity. The inﬂuence of exercise
their research on beta-endorphin which can act as a neurotrans- on endomorphin activity has not yet been investigated; however,
mitter, neuromodulator, and a hormone. Beta-endorphin is found in the injection of endomorphin-1 into the posterior VTA increases
abundance peripherally in the eyes, heart, kidneys, gastrointestinal locomotor activity (Zangen, Ikemoto, Zadina, & Wise, 2002).
tract, and adrenal glands and centrally in the spinal cord and the Opioid modulation of brain dopamine is a central feature in
brain (Imura & Yoshikatsu, 1981). Brain opioid neurons and recep- models of motivated behavior and addiction. One study found that
tors are dense in the arcuate nucleus, with extensive projections c-fos and delta fosB (early genes that induce the expression of other
throughout the brain (e.g., hypothalamus, limbic, periaqueductal regulatory genes) in the nucleus accumbens were activated during
gray, brainstem); in the nucleus tractus solitarius with projections to wheel running in rats and that mice who over express delta fosB
the ventrolateral medulla, and in the ventral tegmental area (VTA) selectively in striatal dynorphin-containing neurons run more than
with projection to basal ganglia such as the ventral pallidum which control litter mates (Werme et al., 2002). Delta fosB could plausibly
modulates hedonics (pleasure related) and approach-avoidance facilitate wheel running by inhibiting the release by GABA neurons
behaviors (see Fig. 1). Opiod receptors are also found in the brain of co-localized dynorphin, which otherwise binds with kappa
frontal cortex and limbic regions such as the amygdala and hippo- opioid receptors to inhibit DA release in the VTA or accumbens
campus that are involved with mood and pain. Beta-endorphin (Werme et al., 2002). Also, neurons that contain the neuropeptide
produces hypoalgesia, respiratory depression, bradycardia, orexin A appear to be involved in opioid-dependent appetitive
contraction of the pupil, hypothermia, and behavioral indifference behavior and increased locomotion (Kotz et al., 2006) by activation
and dependence. Beta-endorphin is secreted into the blood from the of the meso-limbic dopamine pathway between the VTA and the
anterior and intermediate regions of the pituitary during vigorous accumbens (Narita et al., 2006), either by modulating GABAA
receptor-mediated inhibition of the accumbens (Balcita-Pedicino &
exercise depending in part on the intensity of the exercise. It is
Sesack, 2007) or by potentiation of glutamate-N-methyl-D-aspar-
usually accompanied by increases in ACTH, which is derived along
tate (NMDA) receptor-mediated neurotransmission (Borgland,
with beta-endorphin and melanocyte-stimulating hormones from
Taha, Sarti, Fields, & Bonci, 2006) (see Fig. 1). In short, it is plausible
the common precursor pro-opiomelanocortin. Hence, peripheral
that central opioids modulate dopamine and/or other neurotrans-
levels of beta-endorphin during and shortly after acute exercise may
mitter systems that control metabolic or hedonic drives that
be viewed as an indication of the stress response to the exercise.
regulate physical activity.
2. Opioids interact with other neurotransmitter systems
3. A brief history of exercise effects on endorphins and mood
If opioids in the central nervous system do inﬂuence mood
A large volume of research, initiated nearly 30 years ago, linked
responses to exercise, the available evidence indicates that such
the endorphin super-family with disorders of mood and person-
effects will result from complex interactions involving other
ality (Post & Ballenger, 1984; Risch & Pickar, 1983). Endorphins were
neurotransmitter systems implicated in the regulation of mood. For
embraced as an endogenous biologic explanation for the ‘‘runner’s
high’’ (Sachs, 1980) and ‘‘running addiction’’ (Sachs & Pargman,
1979) because of their reported hypoalgesic effects, their opiate-
like structure, and their regulatory roles in central nervous system
function and neuroendocrine response to stress (Collu, Ducharme,
Barbeau, & Tolis, 1982). This acceptance was bolstered by reports
that endorphin-receptor occupancy was altered in rat brain
following acute exercise (Barta, Yashpal, & Henry, 1981; Pert &
Bowie, 1979; Wardlaw & Frantz, 1980); that naloxone, an opioid
receptor antagonist, affected pain perception after jogging (Haier,
Quaid, & Mills, 1981); and that vigorous exercise was accompanied
by increases in plasma leu-enkephalin (Farrell, Gates, Morgan, &
Pert, 1983) and beta-endorphin (Appenzeller, Standefer, Apppenz-
eller, & Atkinson, 1980; Berk, Tan, Anderson, & Reiss, 1981; Bortz
et al., 1981; Colt, Wardlaw, & Frantz, 1981; Farrell, Gates, Maksud, &
Morgan, 1982; Fraioli et al., 1980; Gambert et al., 1981).
Those studies conﬁrmed that plasma endorphins increased with
the stress of acute exercise, and others showed that mood was also
improved post-exercise (e.g., Farrell et al., 1982, 1983; Goldfarb,
Fig. 1. Plausible opioid and early gene modulation of the meso-limbic dopamine
Hatﬁeld, Sforzo, & Flynn, 1987). However, in a study of intense,
system involved with motivation and pleasure.
6 R.K. Dishman, P.J. O’Connor / Mental Health and Physical Activity 2 (2009) 4–9
prolonged cycling exercise among trained cyclists, plasma beta- surveys noted that euphoria was the least common description of
endorphin levels were paradoxically highest in the cyclists that a runner’s high while the most common description involved
reported increased anxiety during exercise (F.J. Galiano, J.M. Davis, perceptions of relaxation (Masters, 1992). Though not well inves-
R.K. Dishman, unpublished observations, May, 1992). Other inves- tigated, a single administration of 100 mg methylenediox-
tigators reasoned that exercise-induced increases in endorphins ymethamphetamine (‘‘ecstacy’’) appears to have about an eight-
might cause positive moods (e.g., reduce anxiety) following exer- fold larger effect on euphoria scores from a well validated
cise. If so, blocking opioid receptors should block the positive mood psychometric instrument (Haertzen & Hickey, 1987) than does
responses to exercise. The earliest investigation of this type showed a single bout of vigorous exercise (Hernandez-Lopez et al., 2002;
that mood elevations after an acute distance run lasting 30 min McGowan, Robertson, & Epstein, 1985).
were not affected by double-blind administration (0.8 mg subcu-
taneously) of naloxone (Markoff, Ryan, & Young, 1982). Subsequent 4. Opioids, nociception and pain
investigations found that blocking opioid receptors using the same
dose of naloxone or 25–50 mg naltrexone blocked (Daniel, Martin, Opioids, located in peripheral, spinal and brain tissue, play
& Carter, 2002; Janal, Colt, Clark, & Glusman, 1984; Jarvekulg & Viru, a central role in modulating (often reducing but sometimes facili-
2002), but also did not block (Allen & Coen, 1987; Farrell et al., 1986; tating) pain (see Fig. 2). Opioids are released in response to stress,
Grossman et al., 1984), improvements in mood following acute injury and pain. Exercise is not only a stressor, but it can produce
exercise. Although questions of effective dosage remained (Haier transient pain in healthy, uninjured people. Leg cycling causes
et al., 1981; Thoren, Floras, Hoffmann, & Seals, 1990), the validity of a highly reproducible pain in the activated muscles, the intensity of
naloxone as an endorphin antagonist during exercise was sup- which depends on the relative exercise intensity and exercise
ported by the ability of an ipsilateral 0.16% naloxone ophthalmic eye duration (Cook, O’Connor, Eubanks, Smith, & Lee, 1997). A survey of
drop to block pupillary miosis characteristic of distance runs 1227 marathon runners found that more than 99% reported pain
exceeding 20 min duration (Allen, Thierman, & Hamilton, 1983). during a marathon (28% reported pain by mile 13), and the average
Because naloxone also increased plasma ACTH and cortisol levels pain intensity at the primary location of pain (legs for most) during
(Volavka, Cho, Mallya, & Bauman, 1979), the weight of the available a marathon run was described as ‘‘strong’’ (O’Connor & Dyke, 2007).
evidence argued that plasma increases in beta-endorphin during Opioids released during vigorous exercise might attenuate pain
intense exercise represented a regulatory response of the anterior caused by muscle contraction, but other algesic substances simul-
pituitary-adrenal axis to the metabolic stress of exercise. taneously produced by exercise could mask such an effect. It has
The plasma beta-endorphin response to acute exercise is char- been reported that none of 60 mg oral codeine, 50 mg oral
acterized by large inter-individual variability (Appenzeller et al., naltrexone or 16 mg iv naloxone altered forearm muscle pain
1980; Farrell et al., 1982, 1983). The dose–response gradient to intensity during high intensity handgrip to fatigue (Cook, O’Connor,
increased exercise intensity (expressed relative to metabolic & Ray, 2000; Ray & Carter, 2007).
capacity) is inconsistent and depends on varying characteristics of However, the effect of opioid blockade on the affective dimen-
both people (e.g., health status, ﬁtness level) and the type of sion of exercise-induced pain has not yet been investigated, and it
exercise (Carr et al., 1981; Farrell et al., 1982; Goldfarb & Jamurtas, appears that opioids have a stronger inﬂuence on this aspect of pain
1997). Although some evidence (Henry, 1982) suggested that compared to pain intensity (Price, Von der Gruen, Miller, Raﬁi, &
a limited amount of circulating endorphins could cross the blood– Price, 1985). Pain measurements made during and after exercise are
brain barrier, such an effect has not been established during exer- potentially useful in part because it is plausible that mood
cise (Sforzo, Seeger, Pert, Pert, & Dotson, 1986). responses to exercise could be inﬂuenced by pain experienced
A few ligand-binding studies of rats produced conﬂicting results during exercise. Moreover, given the possibility that mood
about the effects of exercise on brain endorphins. Opioid receptor responses to exercise are in part or whole a placebo phenomenon, it
binding was higher in several brain regions after 2 h of forced is of potential interest that PET measured alterations in dopamine
swimming, indicative of lower levels of endorphins (Sforzo et al., and opioid release in the nucleus accumbens accounted for
1986). In contrast, brain beta-endorphin levels were higher in the signiﬁcant variation in placebo and nocebo responses to a painful,
nucleus accumbens and leu-enkephalin levels were higher in the non-exercise stressor (Scott et al., 2008).
ventral tegmentum after 2 h of forced treadmill running (Blake, It is also well established that pain responses to a variety of
Stein, & Vomachka, 1984). Because those studies used forced, noxious stimuli (e.g., cold, pressure, electrical stimulation) can be
stressful exercise and did not measure behavioral responses that attenuated during the post-exercise period (Black, Chesher, &
mimic signs of euphoria, reduced anxiety or hypoalgesia, the Starmer, 1979; Koltyn, 2000; Pertovaara, Huppaniemi, Virtanen, &
results neither supported nor refuted the hypothesis that exercise Johansson, 1984), especially following high intensity exercise
affects mood or pain by endorphin mechanisms. Also, chronic (Koltyn, 2002). Mechanisms underlying post-exercise hypoalgesia
treadmill running did not alter basal levels of brain endorphins remain unclear but plausibly could involve opioids acting periph-
(Houghten, Pratt, Young, Brown, & Spann, 1986). In short, there was erally, in the spinal cord, or in the brain (O’Connor & Cook, 1999).
no evidence for a direct link between exercise-induced changes in There is mixed evidence that post-exercise hypoalgesia can be
mood or hypoalgesia and endorphins measured in either the blood reversed using naloxone (Black et al., 1979; Droste, Greenlee,
or the brain (Dishman, 1985). Schrek, & Roskamm, 1991; Haier et al., 1981; Janal, Colt, Clark, &
Another weakness in the argument that endorphins explained Glusman, 1984). Moreover, credible alternative explanations for
the ‘‘runner’s high’’ was the dilemma of deﬁning it, the use of tools post-exercise hypoalgesia have been suggested that may be inde-
with unknown validity to measure it, and the absence of data pendent of opioids, including alterations in attention (Fillingim,
documenting its reproducibility or how it changes during and after Roth, & Haley, 1989) and a reduced willingness to report pain after
exercise. Nearly 30 years ago Michael Sachs, now at Temple exercise (Fuller & Robinson, 1993).
University, found that 27 different adjectives had been used to
describe the ‘‘runner’s high’’ (Sachs, 1980). Early surveys of expe- 5. Synthesis and summary
rienced distance runners reported widely varying estimates of
prevalence ranging from 10% to 78% of runners reporting experi- The hypothesis that endorphins are responsible for changes in
ences of euphoria during a run (Lilliefors, 1978; Sachs, 1980). Later euphoria and other moods during or after acute exercise remains
R.K. Dishman, P.J. O’Connor / Mental Health and Physical Activity 2 (2009) 4–9 7
Fig. 2. Key afferents underlying pain and the opioid pathways involved in pain modulation. Injury or intense exercise activates afferent pathways (in bold) that inform an elaborate
network involved in pain. The network, including sensory and affective aspects of pain can be modulated by an opioid-dependent system in which the periaqueductal gray (PAG)
plays a central role. The PAG integrates information from several brain regions and regulates nociception via projections to the RVM and DLPT. These areas target nociceptive relay
neurons in the dorsal horn of the spinal cord. Opioid receptors are present in the peripheral afferents and all the components of pain modulation system.
plausible, but it has been perpetuated with little evidence. Endor- distance runners who were selected based on their reporting prior
phins play a role in modulating dopamine neurons in parts of the runner’s high experiences. Thus, the link to euphoria in this study is
brain involved with motivation and pleasure and could thus indi- unlikely to generalize to the typical person who exercises, espe-
rectly inﬂuence positive moods. Opiods also are involved in brain cially since most runners don’t routinely report euphoria after
neurotrophic processes induced by voluntary physical activity prolonged exercise (Masters, 1992). It is possible that data from PET,
(Koehl et al., 2008; Persson et al., 2004). Neurotrophic responses and other brain imaging methods, may ultimately help explain
can inﬂuence a broad spectrum of brain-behavior systems, such as some of the variation in mood change associated with running, or
learning and neural plasticity after brain insults (Dishman et al., other types of exercise. However, it will require stronger research
2006), but their importance for understanding mood changes in designs that incorporate larger samples, proper comparison
response to physical activity is not known. conditions, pharmacological manipulation, tight control over the
Plasma endorphin is usually elevated during intense exercise, relative exercise intensity, proper statistical analysis of correlated
but a plausible link between peripheral endorphins and mood changes in mood and opioid binding, the inclusion of valid pain and
responses to acute exercise has not been established. Opioid mood measures, and double-blinding of participants to the study’s
antagonists, which block the effects of endorphins, have not been hypotheses and the investigators to participants’ assignment to
consistent in mitigating positive mood changes after exercise. A experimental condition. Also, a limitation of PET for understanding
direct inﬂuence of peripheral blood endorphin on the brain is mood responses to exercise is the long time it takes to acquire the
limited by the blood–brain barrier. Studies with rats and mice show data. As mood during and after exercise can change from minute to
increased levels of endorphins or enkephalin receptor binding in minute, an understanding of mood responses will require the use of
the brain after acute exercise, but the effects of the levels on brain measurement techniques that have a faster time resolution
behavior, emotion, or physiology were not demonstrated (Hoff- than PET (Boecker, Henriksen, et al., 2008).
mann, 1997) and remain unknown. Despite its innovation, the Boecker study should remind us to
Peripheral endogenous opioids are involved in the modulation avoid the mistakes of past history in prematurely accepting
of nociception and can act on peripheral afferents and spinal a conclusion as the ‘‘truth’’ or ‘‘ﬁnal word’’ when the empirical basis
neurons. Thus, opioid entry into the brain would not be required for is limited or based on false assumptions. For example, we must
an anti-nociceptive effect. The available data do not strongly continue to be cautious about interpreting new discoveries of blood
support the hypothesis that opioids alone cause hypoalgesia during borne responses to exercise (Sparling, Giuffrida, Piomelli, Rosskopf,
or after high intensity exercise. Although opioid-mediated hypo- & Dietrich, 2003; Szabo, Billett, & Turner, 2001; White & Castellano,
algesia (Cook & Koltyn, 2000) could indirectly inﬂuence mood, 2008) as surrogate measures of the brain or as putative explana-
peripheral opioid responses to acute exercise appear to mainly tions for mental outcomes of physical activity (Morgan & O’Connor,
modulate catecholamine inﬂuences on cardiovascular, respiratory, 1988). Likewise, in absence of an adequate research design, clinical
and endocrine responses during exercise (Thoren et al., 1990). An brain imaging studies will neither conﬁrm nor refute mechanisms
effect of peripheral opioids on mood is implausible at present. underlying mental health outcomes of physical activity, regardless
Notwithstanding the limitations of past evidence, the strong of the imprimatur of advanced technology (Boecker, Henriksen,
correlations between self-reports of euphoria and brain opioid et al., 2008; Wang et al., 2000).
binding measured by PET and reported by Boecker et al. (Boecker, Finally, it is important to remember that no single neurotrans-
Sprenger, et al., 2008) (combining data at rest on 1 day and 30 min mitter or neuromodulator system will solely explain states of
after a w 2-h run on a separate day) might provide the seminal consciousness, which depend upon complex interactions of many
advancement for eventually understanding the role of endorphins neural circuits. Likewise, normal ﬂuctuation in human affective
experience, including pain, undoubtedly depends upon regulation
in the subjective experience of vigorous exercise. As far as we know,
of many excitatory and inhibitory neurotransmitters (e.g., acetyl-
this is the ﬁrst and only evidence that brain opioids are inﬂuenced
choline, GABA, and glutamate), neuromodulators (e.g., dopamine,
by exercise in humans. The study participants were 10 experienced
8 R.K. Dishman, P.J. O’Connor / Mental Health and Physical Activity 2 (2009) 4–9
norepinephrine, and serotonin), neurotrophic factors (e.g., BDNF Daniel, M., Martin, A. D., & Carter, J. (2002). Opiate receptor blockade by naltrexone
and mood state after acute physical activity. British Journal of Sports Medicine,
and NGF), neuropeptides besides endorphins (e.g., cholecystokinin,
CRF, galanin, NPY, and VGF), membrane lipids (e.g., endocannabi- De Moor, M. H., Boomsma, D. I., Stubbe, J. H., Willemsen, G., & de Geus, E. J. (2008).
noids), gases (e.g., nitric oxide), and intracellular signaling that Testing causality in the association between regular exercise and symptoms of
anxiety and depression. Archives of General Psychiatry, 65, 897–905.
controls gene transcription and translation, as well as post-trans-
Dishman, R. K. (1985). Medical psychology in exercise and sport. Medical Clinics of
lational regulation of neurons. Pleasure and pain systems, and their North America, 69, 123–143.
associated memories, are fundamental to biological drives that Dishman, R. K. (1997). Brain monoamines, exercise, and behavioral stress: animal
models. Medicine and Science in Sports and Exercise, 29, 63–74.
sustain and perpetuate life and that provide the basis for acquired
Dishman, R. K. (2005). The late arrival of exercise neuroscience. International Journal
motivation and avoidance of danger. Although exogenous phar- of Sport and Exercise Psychology, 3, 255–262.
maceuticals such as opiates, amphetamines, benzodiazepines, and Dishman, R. K., Berthoud, H. R., Booth, F. W., Cotman, C. W., Edgerton, V. R.,
Fleshner, M. R., et al. (2006). Neurobiology of exercise. Obesity (Silver Spring), 14,
tetrahydrocannabinol have strong, direct effects on mood and pain,
equally strong effects by endogenous systems that mimic those Droste, C., Greenlee, M., Schrek, M., & Roskamm, H. (1991). Experimental pain
responses would not be biologically adaptive in the absence of thresholds and plasma beta-endorphin levels during exercise. Medicine Science
in Sports and Exercise, 23, 334–342.
trauma. Hence, it is unusual for people to have euphoric, addictive,
Evans, C. J., Hammond, D. L., & Frederickson, R. C. A. (1988). The opioid peptides. In
or analgesic experiences simply by engaging in physical activity and G. W. Pasternak (Ed.), The opiate receptors (pp. 23–74). Humana Press.
exercise. Why and how physical exertion alters brain neural Farrell, P. A., Gates, W. K., Maksud, M. G., & Morgan, W. P. (1982). Increases in plasma
systems in mentally healthy and unhealthy ways among most ß-endorphin/B-lipotropin immunoreactivity after treadmill running in humans.
Journal of Applied Physiology, 52, 1245–1249.
people, or in special populations, remain experimental curiosities
Farrell, P. A., Gates, W. K., Morgan, W. P., & Pert, C. B. (1983). Plasma leucine
for neuroscience and key questions for public health. enkephalin-like radioreceptor activity and tension-anxiety before and after
competitive running. In H. G. Knuttgen, J. A. Vogel, & J. Poortmans (Eds.),
Biochemistry of exercise (pp. 637–644). Champaign, IL: Human Kinetics
References Farrell, P. A., Gustafson, A. B., Garthwaite, T. L., Kalkhoff, R. K., Cowley, A. W., Jr., &
Morgan, W. P. (1986). Inﬂuence of endogenous opioids on the response of
selected hormones to exercise in humans. Journal of Applied Physiology, 61,
Allen, M. E., & Coen, D. (1987). Naloxone blocking of running-induced mood
changes. Annals of Sports Medicine, 3, 190–195.
Fichna, J., Janecka, A., Costentin, J., & DoRego, J. C. (2007). The endomorphin system
Allen, M., Thierman, J., & Hamilton, D. (1983). Naloxone eye drops reverse the
and its evolving neurophysiological role. Pharmacological Reviews, 59, 88–123.
miosis in runners – implications for an endogenous opiate test. Canadian
Fillingim, R. B., Roth, D. L., & Haley, W. E. (1989). The effects of distraction on the
Journal of Applied Sport Sciences, 8, 99–103.
perception of exercise-induced symptoms. Journal of Psychosomatic Research,
Appenzeller, O., Standefer, J., Appenzeller, J., & Atkinson, R. (1980). Neurology of
endurance training: endorphins. Neurology, 30, 418–419.
Fraioli, F., Moretti, C., Paolucci, D., Alicicco, E., Crescenzi, F., & Fortunio, G. (1980).
Balcita-Pedicino, J. J., & Sesack, S. R. (2007). Orexin axons in the rat ventral
Physical exercise stimulates marked concomitant release of beta-endorphin and
tegmental area synapse infrequently onto dopamine and g-aminobutyric acid
adrenocorticotropic hormone (ACTH) in peripheral blood in man. Experientia,
neurons. Journal of Comparative Neurology, 503, 668–684.
Barta, A., Yashpal, K., & Henry, J. L. (1981). Regional redistribution of B-endorphin in
Fuller, A., & Robinson, R. (1993). A test of exercise induced analgesia using signal
the rat brain: the effect of stress. Proceedings of the Canadian College of Neuro-
detection theory and a within-subjects design. Perceptual and Motor Skills, 776,
Berk, L. S., Tan, S. A., Anderson, C. L., & Reiss, G. (1981). Beta-endorphin response to
Gambert, S. R., Garthwaite, T. L., Pontzen, C. H., Cook, E. E., Tristani, F. E.,
exercise in athletes and non-athletes. [abstract]. Medicine and Science in Sports
Duthie, E. H., et al. (1981). Running elevates plasma beta-endorphin immuno-
and Exercise, 13(5), 134.
reactivity and ACTH in untrained human subjects. Proceedings, Society of
Black, J., Chesher, G. B., & Starmer, G. A. (1979). The painlessness of the long distance
Experimental Biological Medicine, 168, 1–4.
runner. Medical Journal of Australia, 1, 522–523.
Goldfarb, A. H., Hatﬁeld, B. D., Sforzo, G. A., & Flynn, M. G. (1987). Serum beta-
Blake, M. J., Stein, E. A., & Vomachka, A. J. (1984). Effects of exercise training on brain
endorphin levels during a graded exercise test to exhaustion. Medicine and
opioid peptides and serum LH in female rats. Peptides, 5, 953–958.
Science in Sports and Exercise., 19, 78–82.
Boecker, H. (April 3, 2008). Key role of endorphins proven for the ﬁrst time. Jogging
Goldfarb, A. H., & Jamurtas, A. Z. (1997). Beta-endorphin response to exercise. An
really does induce a high! Interview by Dr. Judith Neumaier. MMW Fortschritte
update. Sports Medicine, 24, 8–16.
der Medizin, 150, 17.
Grossman, A., Bouloux, P., Price, P., Drury, P. L., Lam, K. S., Turner, T., et al. (1984). The
Boecker, H., Henriksen, G., Sprenger, T., Miederer, I., Willoch, F., Valet, M., et al.
role of opioid peptides in the hormonal responses to acute exercise in man.
(2008). Positron emission tomography ligand activation studies in the sports
Clinical Science (Colch.), 67, 483–491.
sciences: measuring neurochemistry in vivo. Methods, 45, 307–318.
Haertzen, C. A., & Hickey, J. E. (1987). Addiction Research Center Inventory (ARCI):
Boecker, H., Sprenger, T., Spilker, M. E., Henriksen, G., Koppenhoefer, M.,
measurement of euphoria and other drug effects. In M. A. Bozarth (Ed.),
Wagner, K. J., et al. (2008). The runner’s high: opioidergic mechanisms in the
Methods of assessing the reinforcing properties of abused drugs (pp. 489–524).
human brain. Cerebral Cortex, 18, 2523–2531.
New York: Springer-Verlag.
Borgland, S. L., Taha, S. A., Sarti, F., Fields, H. L., & Bonci, A. (2006). Orexin A in the
Haier, R. J., Quaid, B. A., & Mills, J. S. (1981). Naloxone alters pain perceptions after
VTA is critical for the induction of synaptic plasticity and behavioral sensiti-
jogging. [Letter]. Psychiatric Research, 5, 231–232.
zation to cocaine. Neuron, 49, 589–601.
Hattori, S., Naoi, M., & Nishino, H. (1994). Striatal dopamine turnover during
Bortz, W. M., 2nd, Angwin, P., Mefford, I. N., Boarder, M. R., Noyce, N., & Barchas, J. D.
treadmill running in the rat: relation to the speed of running. Brain Research
(1981). Catecholamines, dopamine, and endorphin levels during extreme
Bulletin, 35, 41–49.
exercise. New England Journal of Medicine, 305, 466–467.
Henry, J. L. (1982). Circulating opioids: possible physiological roles in central
Carr, D. B., Bullen, B. A., Skrinar, G. S., Arnold, M. A., Rosenblatt, M., Beitins, I. Z., et al.
nervous function. Neuroscience and Biobehavioral Reviews, 6, 229–245.
(1981). Physical conditioning facilitates the exercise-induced secretion of beta-
´ ´ ´ ˜
Hernandez-Lopez, C., Farre, M., Roset, P. N., Menoyo, E., Pizarro, N., Ortuno, J., et al.
endorphin and beta-lipotropin in women. New England Journal of Medicine, 305,
(2002). 3,4-Methylenedioxymethamphetamine (ecstasy) and alcohol interac-
tions in humans: psychomotor performance, subjective effects, and pharmaco-
Collu, R., Ducharme, J. P., Barbeau, A., & Tolis, G. (Eds.). (1982). Brain neurotrans-
kinetics. Journal of Pharmacology and Experimental Therapeutics, 300, 236–244.
mitters and hormones. New York: Raven Press.
Hoffmann, P. (1997). The endorphin hypothesis. In W. P. Morgan (Ed.), Physical
Colt, E. W., Wardlaw, S. L., & Frantz, A. G. (1981). The effect of running on plasma
activity and mental health (pp. 163–177). Washington, DC: Taylor & Francis.
beta-endorphin. Life Sciences, 28, 1637–1640.
Holmes, P. V. (2003). Rodent models of depression: reexamining validity without
Cook, D. B., & Koltyn, K. F. (2000). Pain and exercise. International Journal of Sport
anthropomorphic inference. Critical Reviews in Neurobiology, 15, 143–174.
Psychology, 31, 256–277.
Houghten, R. A., Pratt, S. M., Young, E. A., Brown, H., & Spann, D. R. (1986). Effect of
Cook, D. B., O’Connor, P. J., & Ray, C. A. (2000). Muscle pain perception and
chronic exercise on beta-endorphin receptor levels in rats. NIDA Research
sympathetic nerve activity to exercise during opioid modulation. American
Monograph, 75, 505–508.
Journal of Physiology-Integrative and Comparative Physiology, 2279, R1565–
Imura, H., & Yoshikatsu, N. (1981). ‘‘Endorphins’’ in pituitary and other tissues.
Annual Review of Physiology, 43, 265–278.
Cook, D. B., O’Connor, P. J., Eubanks, S. A., Smith, J. C., & Lee, M. (1997). Naturally
Janal, M. N., Colt, E. W., Clark, W. C., & Glusman, M. (1984). Pain sensitivity, mood
occurring muscle pain during exercise: assessment and experimental evidence.
and plasma endocrine levels in man following long-distance running: effects of
Medicine and Science in Sports and Exercise, 29, 999–1012.
naloxone. Pain, 19, 13–25.
Crabbe, J. B., Smith, J. C., & Dishman, R. K. (2007). Emotional & electroencephalo-
Jarvekulg, A., & Viru, A. (2002). Opioid receptor blockade eliminates mood effects of
graphic responses during affective picture viewing after exercise. Physiology &
aerobic gymnastics. International Journal of Sports Medicine, 23, 155–157.
Behavior, 90, 394–404.
R.K. Dishman, P.J. O’Connor / Mental Health and Physical Activity 2 (2009) 4–9 9
Koehl, M., Meerlo, P., Gonzales, D., Rontal, A., Turek, F. W., & Abrous, D. N. (2008). Post, R. M., & Ballenger, J. C. (Eds.). (1984). Neurobiology of mood disorders. Balti-
Exercise-induced promotion of hippocampal cell proliferation requires beta- more: Williams and Wilkins.
endorphin. FASEB Journal, 22, 2253–2262, Epub 2008 Feb 8. Price, D. D., Von der Gruen, A., Miller, J., Raﬁi, A., & Price, C. (1985). A psychophysical
Koltyn, K. (2002). Exercise-induced hypoalgesia and intensity of exercise. Sports analysis of morphine analgesia. Pain, 22, 261–269.
Medicine, 32, 477–487. Ray, C. A., & Carter, J. R. (2007). Central modulation of exercise-induced muscle pain
Koltyn, K. F. (2000). Analgesia following exercise: a review. Sports Medicine, 29, 85–98. in humans. Journal of Physiology, 585, 287–294.
Kotz, C. M., Wang, C., Teske, J. A., Thorpe, A. J., Novak, C. M., Kiwaki, K., et al. (2006). Risch, S. C., & Pickar, D. (Eds.). (1983). Symposium on endorphins. Psychiatric Clinics of
Orexin A mediation of time spent moving in rats: neural mechanisms. Neuro- North America, 6 (pp. 363–521).
science, 142, 29–36. Sachs, M. L. (1980). On the trail of the runner’s high: a descriptive and experimental
investigation of characteristics of an elusive phenomenon. Ph.D. thesis, Florida
Lilliefors, J. (1978). The running mind. Mountain View, CA: World Publications, Inc.
MacRae, P. G., Spirduso, W. W., Walters, T. J., Farrar, R. P., & Wilcox, R. E. (1987).
Sachs, M. L., & Pargman, D. (1979). Running addiction: a depth interview exami-
Endurance training effects on striatal D2 dopamine receptor binding and
nation. Journal of Sport Behavior, 2, 143–155.
striatal dopamine metabolites in presenescent older rats. Psychopharmacology
Scott, D. J., Stohler, C. S., Egnatuk, C. M., Wang, H., Koeppe, R. A., & Zubieta, J. K.
(Berlin), 92, 236–240.
(2008). Placebo and nocebo effects are deﬁned by opposite opioid and dopa-
Markoff, R. A., Ryan, P., & Young, T. (1982). Endorphins and mood changes in long-
minergic responses. Archives of General Psychiatry, 65, 220–231.
distance running. Medicine and Science in Sports and Exercise, 14, 11–15.
Sforzo, G. A., Seeger, T. F., Pert, C. B., Pert, A., & Dotson, C. O. (1986). In vivo opioid
Masters, K. (1992). Hypnotic susceptibility, cognitive dissociation, and runner’s high in
receptor occupation in the rat brain following exercise. Medicine and Science in
a sample of marathon runners. American Journal of Clinical Hypnosis, 34, 193–201.
Sports and Exercise, 18, 380–384.
McGowan, C., Robertson, & Epstein. (1985). The name assigned to the document by
Smith, J. C., & O’Connor, P. J. (2003). Physical activity does not disturb the
the author. This ﬁeld may also contain sub-titles, series names, and report
measurement of startle and corrugator responses during affective picture
numbers. The effect of bicycle ergometer exercise at varying intensities on the
viewing. Biological Psychology, 63, 293–310.
heart rate, EMG and mood state responses to a mental arithmetic stressor.
Sparling, P. B., Giuffrida, A., Piomelli, D., Rosskopf, L., & Dietrich, A. (2003). Exercise
Research Quarterly for Exercise and Sport, 56, 131–137.
activates the endocannabinoid system. Neuroreport, 14, 2209–2211.
Meeusen, R., Piacentini, M. F., & De Meirleir, K. (2001). Brain microdialysis in
Szabo, A., Billett, E., & Turner, J. (2001). Phenylethylamine, a possible link to the
exercise research. Sports Medicine, 31, 965–983.
antidepressant effects of exercise? British Journal of Sports Medicine, 35,
Morgan, W. P. (1997). Chapter 1 – Methodological considerations. In W. P. Morgan
(Ed.), Physical activity and mental health (pp. 3–32). Washington, DC: Taylor &
Thoren, P., Floras, J. S., Hoffmann, P., & Seals, D. R. (1990). Endorphins and exercise:
physiological mechanisms and clinical implications. Medicine and Science in
Morgan, W. P., & O’Connor, P. J. (1988). Exercise and mental health. In R. K. Dishman
Sports and Exercise, 22, 417–428.
(Ed.), Exercise adherence – Its impact on public health (pp. 91–121). Champaign,
Volavka, J., Cho, D., Mallya, A., & Bauman, J. (1979). Naloxone increases
IL: Human Kinetics Publishers.
ACTH and cortisol levels in man. New England Journal of Medicine, 300,
Narita, M., Nagumo, Y., Hashimoto, S., Narita, M., Khotib, J., Miyatake, M., et al.
(2006). Direct involvement of orexinergic systems in the activation of the
Wang, G. J., Volkow, N. D., Fowler, J. S., Franceschi, D., Logan, J., Pappas, N. R., et al.
mesolimbic dopamine pathway and related behaviors induced by morphine.
(2000). PET studies of the effects of aerobic exercise on human striatal dopa-
Journal of Neuroscience, 26, 398–405.
mine release. Journal of Nuclear Medicine, 41, 1352–1356.
O’Connor, P., & Cook, D. (1999). Exercise and pain: the neurobiology, measurement,
Warburton, D. E., Katzmarzyk, P. T., Rhodes, R. E., & Shephard, R. J. (2007). Evidence-
and laboratory study of pain in relation to exercise in humans. Exercise and
informed physical activity guidelines for Canadian adults. Canadian Journal of
Sport Sciences Reviews, 229, 119–166.
Public Health, 98(Suppl. 2), S16–S68.
O’Connor, P. J., & Dyke, J. (2007). Pain experiences during a 26.2 mile marathon run.
Wardlaw, S. L., & Frantz, A. G. (1980). Effect of swimming stress on brain ß-
The Journal of Pain, 9(4), 14, (abstract).
endorphin and ACTS. [abstract]. Clinical Research, 28, 482.
Persson, A. I., Naylor, A. S., Jonsdottir, I. H., Nyberg, F., Eriksson, P. S., & Thorlin, T.
Werme, M., Messer, C., Olson, L., Gilden, L., Thoren, P., Nestler, E. J., et al. (2002).
(2004). Differential regulation of hippocampal progenitor proliferation by
Delta FosB regulates wheel running. Journal of Neuroscience, 22, 8133–8138.
opioid receptor antagonists in running and non-running spontaneously
White, L. J., & Castellano, V. (2008). Exercise and brain health – implications
hypertensive rats. European Journal of Neuroscience, 19, 1847–1855.
for multiple sclerosis: Part 1 – neuronal growth factors. Sports Medicine, 38,
Pert, C. B., & Bowie, D. L. (1979). Behavioral manipulations of rats causes alterations
in opiate receptor occupancy. In E. Usdin, W. E. Bunney, & N. S. Kline (Eds.),
Zangen, A., Ikemoto, S., Zadina, J., & Wise, R. A. (2002). Rewarding and psychomotor
Endorphins in mental health (pp. 93–104). New York: Oxford University Press.
stimulant effects of endomorphin-1: anteroposterior differences within the
Pertovaara, A., Huppaniemi, T., Virtanen, A., & Johansson, G. (1984). The inﬂuence of
ventral tegmental area and lack of effect in nucleus accumbens. Journal of
exercise on dental pain thresholds and the release of stress hormones. Physi-
Neuroscience, 22, 7225–7233.
ology & Behavior, 333, 923–926.