Mental Health and Physical Activity 2 (2009) 4–9

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Mental Health and Physical Activity

Lessons in exercise neurobiology: The case of endorphins

a r t i c l e i n f o a b s t r a c t

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.
Behavioral neuroscience
Limitations of the approaches that have been taken are identified. A key message is that optimal progress
Brain opioids
toward truly understanding the psychological consequences of exercise will require that neuroscience
Central nervous system
Mood 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
positron emission tomography (PET), provided the first evidence 1. Endogenous opioids
that endogenous opioids are released in human brains after
Endogenous opioids (endorphins, enkephalins, and dynorphins)
are peptides that have biochemical properties similar to exogenous
* Corresponding author. Ramsey Center, 330 River Road, Athens, Georgia 30602-
opiates such as heroin and morphine. Endogenous opioids act by
6554, USA. Tel.: þ1 706 542 9840; fax: þ1 706 542 3148. binding to mu, kappa or delta receptors. Because of the widespread
E-mail address: rdishman@uga.edu (R.K. Dishman). distribution of these receptors throughout the peripheral nervous

1755-2966/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mhpa.2009.01.002
 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
exercise depending in part on the intensity of the exercise. It is receptor-mediated inhibition of the accumbens (Balcita-Pedicino &
usually accompanied by increases in ACTH, which is derived along Sesack, 2007) or by potentiation of glutamate-N-methyl-D-aspar-
with beta-endorphin and melanocyte-stimulating hormones from tate (NMDA) receptor-mediated neurotransmission (Borgland,
the common precursor pro-opiomelanocortin. Hence, peripheral Taha, Sarti, Fields, & Bonci, 2006) (see Fig. 1). In short, it is plausible
levels of beta-endorphin during and shortly after acute exercise may that central opioids modulate dopamine and/or other neurotrans-
be viewed as an indication of the stress response to the exercise. mitter systems that control metabolic or hedonic drives that
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
responses to exercise, the available evidence indicates that such A large volume of research, initiated nearly 30 years ago, linked
effects will result from complex interactions involving other the endorphin super-family with disorders of mood and person-
neurotransmitter systems implicated in the regulation of mood. For ality (Post & Ballenger, 1984; Risch & Pickar, 1983). Endorphins were
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
Fig. 1. Plausible opioid and early gene modulation of the meso-limbic dopamine improved post-exercise (e.g., Farrell et al., 1982, 1983; Goldfarb,
system involved with motivation and pleasure. Hatfield, Sforzo, & Flynn, 1987). However, in a study of intense,
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 (Hernández-López 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; Järvekülg & 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
in the subjective experience of vigorous exercise. As far as we know, experience, including pain, undoubtedly depends upon regulation
this is the first and only evidence that brain opioids are influenced of many excitatory and inhibitory neurotransmitters (e.g., acetyl-
by exercise in humans. The study participants were 10 experienced choline, GABA, and glutamate), neuromodulators (e.g., dopamine,
8 R.K. Dishman, P.J. O’Connor / Mental Health and Physical Activity 2 (2009) 4–9

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