The Runner's High: Opioidergic Mechanisms in the Human Brain

Abstract

The runner's high describes a euphoric state resulting from long-distance running. The cerebral neurochemical correlates of exercise-induced mood changes have been barely investigated so far. We aimed to unravel the opioidergic mechanisms of the runner's high in the human brain and to identify the relationship to perceived euphoria. We performed a positron emission tomography "ligand activation" study with the nonselective opioidergic ligand 6-O-(2-[(18)F]fluoroethyl)-6-O-desmethyldiprenorphine ([(18)F]FDPN). Ten athletes were scanned at 2 separate occasions in random order, at rest and after 2 h of endurance running (21.5 +/- 4.7 km). Binding kinetics of [(18)F]FDPN were quantified by basis pursuit denoising (DEPICT software). Statistical parametric mapping (SPM2) was used for voxelwise analyses to determine relative changes in ligand binding after running and correlations of opioid binding with euphoria ratings. Reductions in opioid receptor availability were identified preferentially in prefrontal and limbic/paralimbic brain structures. The level of euphoria was significantly increased after running and was inversely correlated with opioid binding in prefrontal/orbitofrontal cortices, the anterior cingulate cortex, bilateral insula, parainsular cortex, and temporoparietal regions. These findings support the "opioid theory" of the runner's high and suggest region-specific effects in frontolimbic brain areas that are involved in the processing of affective states and mood.

Full text

Cerebral Cortex November 2008;18:2523--2531
doi:10.1093/cercor/bhn013
Advance Access publication February 21, 2008
The Runner’s High: Opioidergic
Mechanisms in the Human Brain
Henning Boecker
1,2
, Till Sprenger
3
, Mary E. Spilker
1
,
Gjermund Henriksen
1
, Marcus Koppenhoefer
1
, Klaus
J. Wagner
4
, Michael Valet
3
, Achim Berthele
3
, and Thomas
R. Tolle
3
1
Nuklearmedizinische Klinik, Klinikum rechts der Isar,
Technische Universita¨ tMu
¨
nchen, 81675 Mu
¨
nchen, Germany,
2
Radiologische Universita¨ tsklinik, FE Klinische Funktionelle
Neurobildgebung, Rheinische Friedrich-Wilhelms-Universita¨ t
Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany,
3
Neurologische Klinik and
4
Klinik fu
¨
r Anaesthesiologie,
Klinikum rechts der Isar, Technische Universita¨ tMu
¨
nchen,
81675 Mu
¨
nchen, Germany
The runner’s high describes a euphoric state resulting from long-
distance running. The cerebral neurochemical correlates of
exercise-induced mood changes have been barely investigated so
far. We aimed to unravel the opioidergic mechanisms of the
runner’s high in the human brain and to identify the relationship to
perceived euphoria. We performed a positron emission tomography
‘‘ligand activation’’ study with the nonselective opioidergic ligand
6-O-(2-[
18
F]fluoroethyl)-6-O-desmethyldiprenorphine ([
18
F]FDPN). Ten
athletes were scanned at 2 separate occasions in random order, at
rest and after 2 h of endurance running (21.5 6 4.7 km). Binding
kinetics of [
18
F]FDPN were quantified by basis pursuit denoising
(DEPICT software). Statistical parametric mapping (SPM2) was used
for voxelwise analyses to determine relative changes in ligand
binding after running and correlations of opioid binding with
euphoria ratings. Reductions in opioid receptor availability were
identified preferentially in prefrontal and limbic/paralimbic brain
structures. The level of euphoria was significantly increased after
running and was inversely correlated with opioid binding in
prefrontal/orbitofrontal cortices, the anterior cingulate cortex,
bilateral insula, parainsular cortex, and temporoparietal regions.
These findings support the ‘‘opioid theory’’ of the runner’s high and
suggest region-specific effects in frontolimbic brain areas that are
involved in the processing of affective states and mood.
Keywords: emotion, exercise, ligand activation, limbic system, opioid, PET
(positron emission tomography), prefrontal, runner’s high
Introduction
Endurance training has been reported to induce a variety of
psychophysical effects, including stress reduction (Rosch
1985), anxiolysis (Morgan 1985), mood elevation (Janal et al.
1984; Wildmann et al. 1986), and reduced pain perception
(Janal et al. 1984). Moreover, there are numerous reports in the
popular and scientific press regarding a state of euphoria while
running, commonly referred to as runner’s high (Wagemaker
and Goldstein 1980; Partin 1983; Morgan 1985). To date, there
is no generally accepted definition as to what runner’s high is,
but common descriptions include feelings like ‘‘pleasantness,’’
‘‘inner harmony,’’ ‘‘boundless energy,’’ or even druglike ‘‘orgias-
tic’’ sensations. The degree of exercise-induced mood change
differs considerably between individuals (Dietrich and McDaniel
2004), and currently, little is known about the mechanisms
mediating euphoria upon physical exercise. The most favored
theory, the ‘‘endorphin hypothesis’’ (Morgan 1985), ascribes
these psychophysical effects to changes in central opioidergic
transmission. The endorphin hypothesis was put forward
because indirect measures such as raised endorphin levels in
peripheral blood (Carr et al. 1981; Gambert et al. 1981; Farrell et al.
1982; Janal et al. 1984; Wildmann et al. 1986) and cerebrospinal
fluid (Radosevich et al. 1989; Hoffmann et al. 1990) as well as the
reversibility of exercise-induced mood changes (Janal et al. 1984),
pain perception (Janal et al. 1984), and pupillary miosis (Allen et al.
1983) by naloxone (unspecific opioid receptor antagonist)
presented strong arguments for an opioidergic involvement.
However, the existence of an ‘‘endorphin driven runner’s high’’
was questioned (Markoff et al. 1982; Dietrich and McDaniel 2004)
because, up to now, the entire basis for the involvement of brain-
derived endorphinergic mechanisms is depicted from measure-
ments of endorphins in the circulating blood.
The aim of this pilot study was to unravel the central
opioidergic mechanisms of the runner’s high and to relate
these changes to perceived euphoria in runners. There are 3
major types of endorphins. b-Endorphins found primarily in the
pituitary gland and released into the blood steam. It is believed
that the resulting plasma changes of endorphins can hardly be
related to central nervous system (CNS) effects because
released endorphins can reenter the brain through the
blood--brain barrier only marginally (Dearman and Francis
1983). The other major representatives of endorphins are the
enkephalins and dynorphin, both distributed throughout many
different structures of the CNS. All the endorphins carry
variable affinities for l, d, and j opioid receptors. It is well
established that b-endorphins display l and d recognition
(Raynor et al. 1994). Whereas l-receptor activation has been
linked to the generation of euphoria, j-receptor activation is
more likely to result in dysphoric mood states (Bodnar 2007).
Due to current lack of clear evidence which receptor subtype
is playing the predominant role for eliciting the runner’s high
sensation in humans and to allow for detecting central
opioidergic activation effects in an exploratory setting, we
employed the tracer 6-O-(2-[
18
F]fluoroethyl)-6-O-desmethyldipre-
norphine ([
18
F]FDPN), a diprenorphine derivative with similar
selectivity to l, d,andj opioid receptors (Wester et al. 2000).
To quantify exercise-induced endogenous opioidergic re-
lease and to determine whether this release is related to mood
changes, we performed 2 positron emission tomography (PET)
scans to compare the [
18
F]FDPN binding under rest and after
strenuous physical exercise. Previous so-called ‘‘ligand activa-
tion’’ studies in the opioidergic system, with and without
experimental challenge, have been successful in identifying
receptor availability changes reflecting endogenous release of
central acting opioidergic peptides (Zubieta et al. 2001).
Because it was previously shown by Zubieta et al. (2003) that
induction of negative mood states is associated with a significant
 The Author 2008. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: journals.per missions @oxf ordjour nals.o rg
by guest on June 6, 2013http://cercor.oxfordjournals.org/Downloaded from

deactivation in l-opioid neurotransmission, we hypothesized
that euphoric mood states would be associated with opioidergic
activation. We also expected a direct relationship between the
level of euphoria and the opioid displacement.
Materials and Methods
Volunteers
We recruited 10 trained male athletes (mean age 36.9 years ± 2.6, range
33--40; mean BMI: 23.1
± 2.1, range 19.9--27.7) from local running and
sports clubs in Munich. Prior to inclusion in the study, each volunteer
answered detailed questionnaires regarding running habits, occurrence
of prior runner’s high--like sensations, baseline demographic informa-
tion, and medical history. As we aimed to investigate the cerebral
correlate of the runner’s high phenomenon, only subjects who affirmed
the presence of previous runner’s high phenomena during and/or after
running were selected. This was the case in all screened subjects. We
had to make sure that the participants were able to complete the
requested 2-h running period safely without adverse effects. For
inclusion in the study, a minimum of 4 h weekly training for the past 2
years was obligatory. The athletes had a mean weekly training of 8.6
±
3.9 h, range 4--10 h. Eight of the 10 athletes had previously completed
marathon races, all of them half-marathons. Participants were informed
about the PET scanning procedure with an opioidergic ligand; however,
they were not informed about the primary outcome parameters of the
study.
Prior to arterial cannulation for invasive blood sampling, perfusion
abnormalities of the 2 major hand vessels were excluded using the
clinical Allen’s test and Doppler ultrasound measurements in each
subject. The study protocol was approved by the local ethics and the
national radiation protection authorities. Written informed consent
according to the Declaration of Helsinki was obtained from each
participant after full explanation of the procedures involved.
Study Design
Each participant underwent 2 [
18
F]FDPN PET scans: a resting state PET
scan (
>
24 h without sportive activity) and a post exercise PET scan 30
min after running. The participating volunteers were randomly assigned
to the order of the 2 PET conditions (6 subjects with initial rest scan,
4 subjects with initial postrun scan), and all PET scans were performed
at the same time of the day (~1:00--3:30 PM). The mean time interval
between the 2 [
18
F]FDPN PET scans was 4.0 ± 1.9 weeks. Prior to each
PET scan, a toxicological urine screening for cannabinoids and opioids
ruled out substance abuse.
The current affective states before and after running as well as before
the resting PET scan were evaluated with Visual Analog Mood Scales
(VAMS; Aitken 1969). For the different items (sadness, tension, fear,
anger, confusion, fatigue, happiness, and energy; Stern et al. 1997),
subjects had to rate their current affective state: for example, ‘‘How is
your sadness right now?’’ The verbal descriptors at the end of the visual
analog scale (VAS) were as follows: *no sadness at all *on the left side
versus *strongest sadness imaginable *on the right side. Accordingly,
the descriptors for euphoria were, no euphoria at all versus strongest
euphoria imaginable. The VAMS score was determined by measuring
the distance in millimeters from the left end of the scale to the
participants mark.
After the volunteers had completed the PET part of the study, they
performed 2 additional 2-h runs at home under their typical training
circumstances to gain rating data (VAS euphoria scale) under natural
conditions.
[
18
F]FDPN Synthesis and PET Methodology
The procedures used for synthesis of [
18
F]FDPN have been previously
described in detail (Wester et al. 2000). Compared with the radioligand
[
11
C]DPN (t
1/2
, C-11 = 20 min), [
18
F]FDPN has the advantage of a longer
half-life (t
1/2
, F-18 = 109.7 min) and improved signal intensity (Wester
et al. 2000). The specific activity obtained was
>
37 TBq/mmol. The PET
scans were acquired on a Siemens/CTI ECAT EXACT HR
+
scanner
(Knoxville, TN) in 3D mode with septa retracted. The PET scanner has
a field of view covering 15.5 cm. A neck shield (NeuroShield, Scanwell
Systems, Lavigne, St Montreal, Canada) was used to reduce random
count rates. The attenuation was corrected using transmission scanning
prior to the [
18
F]FDPN studies. The acquired data were reconstructed
using filtered backprojection with a ramp filter (cut off 0.3 cycles per
projection element) into 63 image planes with a 128
3 128 pixel image
matrix.
[
18
F]FDPN was administered as a single bolus intravenous injection
(2.5 mCi), and PET images were acquired over 120 min with the
following frame durations: 12
3 10 s; 3 3 20 s; 7 3 1 min; 4 3 2 min; and
20 3 5 min for a total of 46 frames. Arterial blood and metabolite
samples were taken regularly throughout the scanning period for
metabolite correction and quantitative modeling. The amount of intact
tracer as a function of time was determined according to the published
procedure (Wester et al. 2000) and subsequently used to calculate the
metabolite-corrected arterial input function as described previously
(Spilker et al. 2004).
Data Analysis
Each subject’s dynamic PET data set was realigned to a scan with a high
signal to noise ratio using a fourth degree B-spline interpolation and
resliced to reduce motion artifacts during the scan. The dynamic
volumes were then normalized to a ligand-specific template (Meyer and
Ichise 2001). These preprocessing steps were performed using
Statistical parametric mapping (SPM2) (Wellcome Department of
Imaging Neuroscience, London, United Kingdom). Our previous work
has indicated that the distribution volume (DV) of [
18
F]FDPN can be
accurately determined after metabolite-corrected arterial sampling and
dynamic PET acquisitions over at least 90 min (Spilker et al. 2004;
Boecker et al. 2005). Binding kinetics were quantified by basis pursuit
denoising as implemented in the DEPICT software (Gunn et al. 2002).
This basis function method is a data-driven modeling approach where
no a priori structure is assumed to characterize the data. Instead, an
impulse response function is generated from a sum of exponentials that
describes the data, given the input function. The DV is then determined
from the integral of the impulse response function. The resulting DV
images were smoothed using an isotropic Gaussian kernel of 10 mm full
width at half maximum.
Changes in ligand binding after the running period were assessed
using a paired t-test in SPM2. As the process of absolute quantification
of opioid receptor binding relies on a complex methodology (e.g.,
arterial blood sampling) with several theoretical sources of error, we
used proportional scaling to compensate between-scan differences in
global DV values. The resulting maps of t-statistics were transformed to
the unit normal distribution SPM and thresholded at an uncorrected
height threshold of P
<
0.001 and P
<
0.05, corrected for false-positives
(false discovery rate [FDR]) correction (Genovese et al. 2002). Both
threshold criteria had to be reached for a voxel to be considered
significant.
In a second step, a covariation analysis accounting for differences in
scan order (i.e., covariate of no interest) between opioidergic ligand
binding (DV) and the postrunning euphoria ratings (VAS immediately
before the PET scanning) was performed. The threshold for this
regression analysis was P
<
0.001, uncorrected; significance of regions
surpassing this uncorrected height threshold was determined by small
volume correction (10 voxel sphere). The anatomical localization of
the activation peaks was determined by transforming the 3D
coordinates from Montreal Neurological Institute space in Talairach
space (Talairach and Tournoux 1988) using the mni2tal tool (MRC
Cognition and Brain Sciences Unit, Cambridge, England; http://
imaging.mrc-cbu.cam.ac.uk/imaging/MniTalairach).
Results
Running Performance
The running exercise was completed after 115
± 6.8 min at an
average pace of 11.0
± 2.3 km/h and an average running
distance of 21.5
± 4.7 km. The average heart rate during
exercise was 144
± 7 min
-1
(morning resting values in supine
position: 52
± 11 min
-1
). At the time immediately prior to
2524 Opioidergic Release in Long-Distance Running
d
Boecker et al.
by guest on June 6, 2013http://cercor.oxfordjournals.org/Downloaded from

injection of the PET tracer (i.e., 30 min after running), there
were no significant differences regarding heart rate (1-sided
paired t-test, P
= 0.097), systolic (P = 0.099), and diastolic
(P
= 0.302) arterial blood pressure.
Behavioral Ratings
On the VAS ratings of the 9 mood-related items (Stern et al.
1997), the euphoria ratings and the happiness ratings were the
only items that showed a significant change (Fig. 1) with
exercise: The euphoria ratings increased from 37.6
± 19.6/100
(prior to exercise) to 73.3
± 13.2/100 (after exercise: 2-tailed
paired t-test, P
<
0.05 with correction for multiple compar-
isons). This increase was also significant when compared with
the ratings during rest on the day of the baseline scan (28.5
±
17.4/100, 2-tailed paired t-test, P
<
0.05 with correction for
multiple comparisons). The prerun VAS euphoria ratings were
not significantly different compared with the VAS euphoria
rating on the resting day (37.6
± 19.6/100 vs. 28.5 ± 17.4/100;
not significant after correction for multiple comparisons).
Similar significant modulations were observed on the happiness
scores, with significant increases after running compared with
the ratings prior to exercise as well as during rest on the day of
the baseline scan (2-tailed paired t-test, P
<
0.05 with
correction for multiple comparisons). No pain sensations were
reported during or after the physical exercise by any of the
participating runners.
To assure that the VAS ratings were not biased by the
scanning procedure, we acquired additional euphoria ratings
after identical running exercises on 3 different days under
natural (normal training) conditions (N
= 10). Subjects were
informed about these additional ratings after completion of the
PET scans. The ratings of euphoria showed nearly parallel
changes under normal training conditions and were compara-
ble to the values obtained on the days of the PET scanning
(2-tailed paired t-tests at prerun (P
= 0.8) and at postrun
(P
= 0.9) time points, both not significant).
Main Effect of Running on Opioidergic Activation
[
18
F]FDPN binding (DV) decreased significantly (uncorrected
height threshold
<
0.001, FDR correction of suprathreshold
voxels
<
0.05) after physical exercise (PET scan starting 30 min
after running) in widespread cortical brain areas including
prefrontal/orbitofrontal cortices, dorsolateral prefrontal cor-
tex, anterior and posterior cingulate cortex, insula and para-
hippocampal gyrus, and sensorimotor/parietal regions (Fig. 2).
Subcortical [
18
F]FDPN binding (DV) decreases were observed
in cerebellum and basal ganglia. No significant increases of
[
18
F]FDPN binding were observed after endurance training
(identical threshold as for decreases). Table 1 summarizes all
regions with decreased [
18
F]FDPN binding after exercise.
Relationship of Opioidergic Activation and Affective
Modulation
Having established the presence of [
18
F]FDPN binding reduc-
tions in the brain after endurance training, we sought to
investigate whether the degree of ligand binding correlated
with the individual VAS euphoria ratings, which changed
significantly with running. The regression analysis indicated
that the VAS ratings of euphoria were inversely correlated with
[
18
F]FDPN binding in prefrontal/orbitofrontal cortices, the
anterior cingulate cortex, bilateral insula and parainsular
cortex, along with temporoparietal regions (uncorrected
height threshold
<
0.001, significant after small volume correc-
tion using 10 voxel sphere; Table 2 and Fig. 3). Figure 4 is
a composite of the SPM correlation analysis with scatter plots
from 3 selected regions showing how the VAS euphoria ratings
are correlated with the tracer binding. No significant positive
correlations of [
18
F]FDPN binding and VAS euphoria ratings
were observed.
Discussion
Exercise-induced changes in mood were described as being
a consequence of alterations in endogenous opioid release.
Because objective demonstration of central opioidergic release
was precluded for technical and ethical reasons, up to now, the
‘‘opioid hypothesis’’ was based entirely on findings of enhanced
endorphins levels in the peripheral blood. To disclose the
central opioidergic mechanisms and to identify a relationship
to perceived euphoria during strenuous exercise, we per-
formed a PET ligand activation study with the nonspecific
opioidergic ligand [
18
F]FDPN. This study succeeded in demon-
strating regional specific changes in opioid binding after
strenuous exercise, thereby providing a basis for understanding
the link between exercise-induced psychophysical effects and
changes in central opioidergic neurotransmission. Changes in
central opioid receptor binding after 2 h of long-distance
running were identified preferentially in prefrontal and limbic/
paralimbic brain regions. Specifically, the perceived levels of
euphoria were inversely correlated with opioid binding in
prefrontal/orbitofrontal cortices, the anterior cingulate cortex,
bilateral insula, and parainsular cortex, along with temporopar-
ietal regions.
For decades, the mechanisms underlying euphoria during
and after sustained endurance training have captured the
interest of scientists. Participation of central opioidergic
pathways has been suggested based on work in rats showing
that running can alter opiate cerebrospinal fluid levels
(Hoffmann et al. 1990) and receptor occupancy (Tendzegolskis
Figure 1. Box plot of euphoria VAS scores. Mean and standard error of VAMS
ratings (0--100) during 2 conditions (left column of each item represents rest, right
column postexercise). Differences between the conditions were significant for the
items euphoria and happiness (Student’s paired t-test, P \ 0.05, corrected for
multiple comparisons).
Cerebral Cortex November 2008, V 18 N 11 2525
by guest on June 6, 2013http://cercor.oxfordjournals.org/Downloaded from

et al. 1991; Aravich et al. 1993). On the behavioral level, it
has been demonstrated in mice subjected to a regular
swimming schedule that naloxone induces withdrawal symp-
toms similar to those following chronic morphine treatment
(Christie and Chesher 1982) and forced swimming in
cold water has been shown to cause brain decreases in
[3H]diprenorphine binding (Seeger et al. 1984). In humans,
however, the closest information gathered thus far on exercise-
induced opioidergic mechanisms was derived from peripheral
blood. Different research groups have reported up to 5-fold
increases of plasma b-endorphin levels after physical exercise
(Carr et al. 1981; Farrell et al. 1982; Wildmann et al. 1986).
Figure 2. Reductions in opioidergic receptor availability after endurance running in comparison with the rest condition. Statistical parametric maps of the categorical comparison
(regions where [
18
F]FDPN binding is reduced after physical exercise) in standard stereotactic space (Montreal Neurological Institute [MNI] space) are overlaid in color on axial
slices of a skull-stripped normalized brain (MNI single subject brain as provided by MRIcro program). Z values indicate the location of the slice planes relative to the AC--PC line.
For display purposes, the statistical analysis is thresholded at an uncorrected height threshold of P \ 0.001. L, left side of figure; R, right side of figure. The signal in the left
ventricle is supposed to represent an artifact because this region is devoid of opioid receptors.
2526 Opioidergic Release in Long-Distance Running
d
Boecker et al.
by guest on June 6, 2013http://cercor.oxfordjournals.org/Downloaded from

However, peripheral opioid levels most likely do not reflect
those in the CNS (Rossier et al. 1977; Dietrich and McDaniel
2004).
The measured DV changes cannot be erroneously attributed
to running-associated changes in systemic cardiovascular
measures because blood pressure and heart rate were reverted
to resting levels at the time of tracer injection (approximately
30 min postexercise). Mechanisms such as receptor internal-
ization or downregulation might potentially add to the reduced
DV values (Laruelle 2000; Sprenger et al. 2005). However, this
would also be indicative of receptor activation by endogenous
opioidergic ligands and add to the observation of opioidergic
neurotransmission in the brain areas with reduced DV values.
Moreover, the absence of pain or discomfort during and after
exercise (see Results), argues against any potentially confound-
ing pain-related releases of endogenous opioids (Zubieta et al.
2001; Sprenger et al. 2006). Although recent work by Hume
et al. (2007) has questioned the suitability of radiolabeled
diprenorphine to depict changes in opioid binding after
application of exogenous/synthetic opioid, we are convinced
that [
18
F]FDPN is a suitable ligand to detect changes in opioid
receptor binding induced by release of endogenous opioids,
such as in endurance running because a previous autoradio-
graphic study using [3H]diprenorphine evidenced stress-in-
duced decreases in opioid receptor binding in the rat brain
(Seeger et al. 1984). Furthermore, we have previously shown in
humans using [
18
F]FDPN pain-related opioidergic activation
using this ligand (Sprenger et al. 2006).
It is shown here (Fig. 2) that the endogenous release of
central opioids occurs preferentially in brain regions belonging
to frontolimbic circuits that are known to play a key role in
emotional processing (Dalgleish 2004). Importantly, no signif-
icant increases in [
18
F]FDPN ligand binding were detected.
Hence, the main effect of physical exercise on opioidergic
release is fundamentally different compared with induction of
temporary sadness states, as elicited by recall of emotionally
negative autobiographical events (Zubieta et al. 2003). Whereas
sadness states are associated with deactivations in l-opioid
neurotransmission in limbic structures (including rostral
anterior cingulate, ventral pallidum, and amygdala), physical
exercise is associated with opioidergic activation in frontolim-
bic brain regions.
It can be assumed that euphoria is associated with reward,
especially in runners with repetitive experiences of euphoric
sensations related to endurance training. Hence, one might
have expected changes in opioidergic neurotransmission in the
nucleus accumbens, a key structure for reward processing with
known opioid--dopamine interactions. Although we did not
observe relevant running-related opioidergic changes in this
brain structure, it might be feasible to detect such changes in
the dopaminergic system. This has been attempted by Wang
et al. (2000) using [
11
C]raclopride PET to study striatal
dopamine release in healthy volunteers running on a treadmill
for 30 min. These authors could not show such changes in the
dopaminergic system. However, no psychophysical data were
acquired and it is therefore not clear whether the treadmill
running induced euphoria and/or reward in these volunteers.
Therefore, it remains to be shown how the dopaminergic
system behaves in prolonged physical exercise with induction
of euphoria, as studied here.
Table 1
Reductions in opioidergic receptor availability after endurance running in comparison with the
rest condition
Brain region K (cluster
size)
t values Z scores x, y , z (mm)
Talairach
coordinates
Frontal areas
Right inferior frontal gyrus, BA 47 715 12.40 5.00 38, 21,  15
Left middle frontal gyrus, BA 10 60 8.75 4.40 34, 49, 4
Medial frontal gyrus, BA 6 154 8.55 4.36 0, 16, 46
Right inferior frontal gyrus, BA 9 206 6.92 3.98 58, 17, 22
Right middle frontal gyrus, BA 9 5.86 3.67 46, 27, 29
Right middle frontal gyrus, BA 46 5.14 3.43 52, 23, 21
Left middle frontal gyrus, BA 9 92 6.61 3.90 38, 17, 27
Right middle frontal gyrus, BA 46 31 5.52 3.56 46, 39, 23
Right middle frontal gyrus, BA 11 65 5.42 3.53 38, 50, 11
Right middle frontal gyrus, BA 10 4.92 3.34 36, 58, 13
Right middle frontal gyrus, BA 10 35 4.98 3.37 4, 53, 8
Limbic/paralimbic areas
Right posterior cingulate, BA 31 384 7.75 4.19 4, 32, 33
Right middle cingulate gyrus 6.52 0.87 14, 14, 38
Left parahippocampal gyrus, BA 35 45 7.38 4.10 20, 13, 25
Left parahippocampal gyrus, BA 28 5.63 3.60 22, 19, 18
Right anterior cingulate, BA 32 224 7.04 4.01 4, 44, 13
Left superior temporal gyrus/insula 34 6.91 3.98 46, 18,  8
Left insula 33 5.66 3.61 44, 23, 24
Temporoparietal areas
Right fusiform gyrus, BA 37 371 9.16 4.48 34, 52, 15
Right postcentral gyrus, BA 5 291 8.44 4.34 38, 44, 56
Right inferior parietal lobule, BA 40 7.39 4.10 46, 33, 57
Right superior parietal lobule, BA 7 119 8.01 4.24 42, 58, 53
Left inferior parietal lobule, BA 40 184 7.72 4.18  46, 41, 45
Right precuneus, BA 7 133 7.62 4.15 8, 64, 42
Right precuneus, BA 31 4.92 3.35 4, 47, 34
Left precuneus, BA 19 57 7.41 4.10 32, 76, 37
Right superior temporal gyrus, BA 21 512 7.40 4.10 64, 20, 1
Left fusiform gyrus, BA 37 194 6.60 3.89 50, 55, 10
Right precentral gyrus, BA 4 103 6.16 3.76 60, 9, 23
Subcortical areas
Right cerebellum, anterior lobe 147 7.40 4.10 16, 48, 12
Left caudate nucleus 97 9.64 4.57 10, 19, 24
Right cerebellum, posterior lobe 37 6.43 3.84 20, 80, 29
Left lentiform nucleus 59 6.11 3.75 26, 14, 7
The statistical analysis is thresholded at an uncorrected height threshold of P \ 0.001 and P \
0.05 corrected for false positives (FDR correction). The regions are grouped according to location.
BA, Brodmann area; K, cluster size (number of voxels).
Table 2
Correlation of opioidergic binding in runners with VAS ratings of euphoria
Brain region K (cluster
size)
t values Z scores x, y , z (mm)
Talairach
coordinates
Frontal areas
Left middle frontal gyrus, BA 9 45 4.12 3.35 38, 19, 30
Right superior frontal gyrus, BA 9 95 4.10 3.34 18, 46, 18
Right superior frontal gyrus, BA 11 66 4.07 3.32 32, 56, 15
Right medial frontal gyrus, BA 10 87 3.96 3.26 14, 61, 8
Right inferior frontal gyrus, BA 47 50 3.82 3.17 57, 18, 11
Limbic/paralimbic areas
Right anterior cingulate 95 3.83 3.18 10, 38, 15
Right insula/superior temporal gyrus 148 4.92 3.79 54, 2, 4
Left insula/superior temporal gyrus 115 4.25 3.42 46, 14, 8
Left insula 90 3.77 3.15 48, 26, 18
Left insula 69 3.77 3.14 38, 19, 6
Temporoparietal areas
Left inferior parietal lobule, BA 40 154 5.28 3.96 52, 40, 46
Left precuneus, BA 19 45 4.56 3.60  30, 78, 35
Left fusiform gyrus 113 4.46 3.54 22, 66, 5
Right superior temporal gyrus, BA 13 91 4.44 3.53 52, 42, 15
Right fusiform gyrus, BA 37 72 4.03 3.30 38, 59, 11
The statistical analysis is thresholded at P \ 0.001, uncorrected. All regions are also significant
after small volume correction (10 voxel sphere). The regions are grouped according to location.
BA, Brodmann area; K, cluster size (number of voxels).
Cerebral Cortex November 2008, V 18 N 11 2527
by guest on June 6, 2013http://cercor.oxfordjournals.org/Downloaded from

Beyond these main effects of opioidergic activation, we were
able to demonstrate that the amount of opioidergic release in
frontolimbic brain structures is tightly linked to the degree of
affective modulation (Figs 3 and 4). This is reflected by the
inverse correlation between [
18
F]FDPN binding and the VAS
euphoria ratings in the prefrontal/orbitofrontal cortices, the
anterior cingulate cortex, and the insula/parainsular cortex
(Table 2 and Fig. 4). Knowing that frontolimbic circuits are
pivotal for the generation of affect and mood states, we
conclude that this differential release of endogenous opioids in
relation to perceived euphoria is very likely responsible for the
generation of the runner’s high sensation. Euphoria-related
Figure 3. Correlation of opioidergic binding in runners with VAS ratings of euphoria. Statistical parametric maps of the regression analysis (regions where VAS ratings of euphoria
are inversely correlated with [
18
F]FDPN binding) in standard stereotactic space (Montreal Neurological Institute [MNI] space) are overlaid in color on axial slices of a skull-stripped
normalized brain (MNI single subject brain as provided by MRIcro program). Z values indicate the location of the slice planes relative to the AC--PC line. For display purposes, the
statistical analysis is thresholded at an uncorrected height threshold of P \ 0.001. All regions are also significant after small volume correction (10 voxel sphere). L, left side of
figure; R, right side of figure.
2528 Opioidergic Release in Long-Distance Running
d
Boecker et al.
by guest on June 6, 2013http://cercor.oxfordjournals.org/Downloaded from

effects were also noted in the fusiform gyrus, a brain region
responding to different emotional expressions (Geday et al.
2003; Winston et al. 2003; Baumgartner et al. 2006) and even
recapitulation of emotions (Fenker et al. 2005).
The applied receptor ligand [
18
F]FDPN labels mu, kappa, and
delta opioid receptors in a nonspecific way. Therefore, no
conclusion can be drawn from our data, with respect to which
of these opioid receptors is dominating the opioidergic effects
related to endurance training. As antinociceptive effects in
runners have been described (Janal et al. 1984; Koltyn 2000)
and these effects are thought to be predominantly mu-
dependent, it might be deduced that the observed changes in
opioid receptor availability are at least partly l related. Further
studies will have to clarify the specific contribution of the
Figure 4. Correlation of opioidergic binding in runners with VAS ratings of euphoria. Scatter plots of opioid receptor binding (DV) with individual VAS euphoria ratings (VAS post
run) are shown from 3 regions (top row: right anterior cingulate cortex, ACC; middle row: right orbitofrontal cortex, OFC; bottom row: right insula, INS). The [
18
F]FDPN binding in
the respective areas is plotted in relation to perceived euphoria (abscissa: VAS rating from 0--100, ordinate: SPM-scaled DV values). The SPMs are overlaid in color on axial,
coronal, and transversal sections of a stereotactically normalized brain (Montreal Neurological Institute single subject brain as provided by SPM2). For display purposes, the
statistical analysis is thresholded at an uncorrected height threshold of P \ 0.001.
Cerebral Cortex November 2008, V 18 N 11 2529
by guest on June 6, 2013http://cercor.oxfordjournals.org/Downloaded from

different opioid receptor types. This is of particular interest as
the different opioid receptor types have complex and partly
opposing functions not only in nociception but also in the
modulation of mood states.
In conclusion, this study provides first in vivo evidence that
release of endogenous opioids occurs in frontolimbic brain
regions after sustained physical exercise and that there is its
close correlation to perceived euphoria of runners. This
suggests a specific role of the opioid system in the generation
of the runner’s high sensation. In a more general view, it might
also be assumed that opioidergic effects in frontolimbic brain
structures mediate not only some of the therapeutically
beneficial consequences of endurance exercise on depression
and anxiety in patients (Morgan 1985) but also the addictive
aspects of excessive sports, where injured athletes continue
their training in spite of detrimental consequences to their
health (Chapman and De Castro 1990). Such phenomena will
have to be addressed in future studies focusing on not only
physical exercise, mood, and reward but also interactions
between endogenous opioids and other neurotransmitter
systems and modulators, particularly dopamine and endocan-
nabinoids (Dietrich and McDaniel 2004; Gardner 2005).
Funding
Deutsche Forschungsgesellschaft (SFB 391, TP C9); the
Kommission fu
¨
r Klinische Forschung (8764153) at the Klinikum
rechts der Isar, Mu
¨
nchen; by the German Research Network on
Neuropathic Pain (DFNS) of the Federal Ministry of Education
and Research (BMBF).
Notes
We would like to acknowledge the work of our colleagues Brigitte
Dzewas and Choletta Kruschke for their technical assistance during
PET scanning as well as the assistance of Prof. Dr Thomas Jahn
(Department of Psychiatry, Klinikum rechts der Isar, TU Mu
¨
nchen)
regarding the behavioral evaluations. We particularly acknowledge the
help of Dr A. Fricke in the recruitment of the volunteers. Conflict of
Interest : None declared.
Address correspondence to email: henning.boecker@ukb.uni-bonn.de.
References
Aitken RC. 1969. Measurement of feelings using visual analogue scales.
Proc R Soc Med. 62:989--993.
Allen M, Thierman J, Hamilton D. 1983. Naloxone eye drops reverse the
miosis in runners--implications for an endogenous opiate test. Can J
Appl Sport Sci. 8:98--103.
Aravich PF, Rieg TS, Lauterio TJ, Doerries LE. 1993. Beta-endorphin and
dynorphin abnormalities in rats subjected to exercise and restricted
feeding: relationship to anorexia nervosa? Brain Res. 622:1--8.
Baumgartner T, Lutz K, Schmidt CF, Jancke L. 2006. The emotional
power of music: how music enhances the feeling of affective
pictures. Brain Res. 1075:151--164.
Bodnar RJ. 2007. Endogenous opiates and behavior: 2006. Peptides.
28:2435--2513.
Boecker H, Sprenger T, Henriksen G, Toelle TR, Spilker ME. 2005.
Optimal duration of PET studies with 18F-fluoroethyl-diprenorphine.
J Nucl Med. 46:2092--2096.
Carr DB, Bullen BA, Skrinar GS, Arnold MA, Rosenblatt M, Beitins IZ,
Martin JB, McArthur JW. 1981. Physical conditioning facilitates the
exercise-induced secretion of beta-endorphin and beta-lipotropin in
women. N Engl J Med. 305:560--563.
Chapman CL, De Castro JM. 1990. Running addiction: measurement and
associated psychological characteristics. J Sports Med Phys Fitness.
30:283--290.
Christie MJ, Chesher GB. 1982. Physical dependence on physiologically
released endogenous opiates. Life Sci. 30:1173--1177.
Dalgleish T. 2004. The emotional brain. Nat Rev Neurosci. 5:583--589.
Dearman J, Francis KT. 1983. Plasma levels of catecholamines, cortisol,
and beta-endorphins in male athletes after running 26.2, 6, and
2 miles. J Sports Med Phys Fitness. 23:30--38.
Dietrich A, McDaniel WF. 2004. Endocannabinoids and exercise. Br
J Sports Med. 38:536--541.
Farrell PA, Gates WK, Maksud MG, Morgan WP. 1982. Increases in
plasma beta-endorphin/beta-lipotropin immunoreactivity after
treadmill running in humans. J Appl Physiol. 52:1245--1249.
Fenker DB, Schott BH, Richardson-Klavehn A, Heinze HJ, Duzel E. 2005.
Recapitulating emotional context: activity of amygdala, hippocam-
pus and fusiform cortex during recollection and familiarity. Eur
J Neurosci. 21:1993--1999.
Gambert SR, Garthwaite TL, Pontzer CH, Cook EE, Tristani FE,
Duthie EH, Martinson DR, Hagen TC, McCarty DJ. 1981. Running
elevates plasma beta-endorphin immunoreactivity and ACTH in
untrained human subjects. Proc Soc Exp Biol Med. 168:1--4.
Gardner EL. 2005. Endocannabinoid signaling system and brain reward:
emphasis on dopamine. Pharmacol Biochem Behav. 81:263--284.
Geday J, Gjedde A, Boldsen AS, Kupers R. 2003. Emotional valence
modulates activity in the posterior fusiform gyrus and inferior
medial prefrontal cortex in social perception. Neuroimage.
18:675--684.
Genovese CR, Lazar NA, Nichols T. 2002. Thresholding of statistical
maps in functional neuroimaging using the false discovery rate.
Neuroimage. 15:870--878.
Gunn RN, Gunn SR, Turkheimer FE, Aston JA, Cunningham VJ. 2002.
Positron emission tomography compartmental models: a basis
pursuit strategy for kinetic modeling. J Cereb Blood Flow Metab.
22:1425--1439.
Hoffmann P, Terenius L, Thoren P. 1990. Cerebrospinal fluid
immunoreactive beta-endorphin concentration is increased by
voluntary exercise in the spontaneously hypertensive rat. Regul
Pept. 28:233--239.
Hume SP, Lingford-Hughes AR, Nataf V, Hirani E, Ahmad R, Davies AN,
Nutt DJ. 2007. Low sensitivity of the positron emission tomography
ligand [11C]diprenorphine to agonist opiates. J Pharmacol Exp Ther.
322:661--667.
Janal MN, Colt EW, Clark WC, Glusman M. 1984. Pain sensitivity, mood
and plasma endocrine levels in man following long-distance
running: effects of naloxone. Pain. 19:13--25.
Koltyn KF. 2000. Analgesia following exercise: a review. Sports Med.
29:85--98.
Laruelle M. 2000. Imaging synaptic neurotransmission with in vivo
binding competition techniques: a critical review. J Cereb Blood
Flow Metab. 20:423--451.
Markoff RA, Ryan P, Young T. 1982. Endorphins and mood changes in
long-distance running. Med Sci Sports Exerc. 14:11--15.
Meyer JH, Ichise M. 2001. Modeling of receptor ligand data in PET and
SPECT imaging: a review of major approaches. J Neuroimaging.
11:30--39.
Morgan WP. 1985. Affective beneficence of vigorous physical activity.
Med Sci Sports Exerc. 17:94--100.
Partin C. 1983. Runner’s ‘‘high.’’ JAMA. 249:21.
Radosevich PM, Nash JA, Lacy DB, O’Donovan C, Williams PE,
Abumrad NN. 1989. Effects of low- and high-intensity exercise on
plasma and cerebrospinal fluid levels of ir-beta-endorphin, ACTH,
cortisol, norepinephrine and glucose in the conscious dog. Brain
Res. 498:89--98.
Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T. 1994.
Pharmacological characterization of the cloned kappa-, delta-, and
mu-opioid receptors. Mol Pharmacol. 45:330--334.
Rosch PJ. 1985. Exercise and stress reduction. Compr Ther. 11:10--15.
Rossier J, French ED, Rivier C, Ling N, Guillemin R, Bloom FE. 1977.
Foot-shock induced stress increases beta-endorphin levels in blood
but not brain. Nature. 270:618--620.
Seeger TF, Sforzo GA, Pert CB, Pert A. 1984. In vivo autoradiography:
visualization of stress-induced changes in opiate receptor occu-
pancy in the rat brain. Brain Res. 305:303--311.
2530 Opioidergic Release in Long-Distance Running
d
Boecker et al.
by guest on June 6, 2013http://cercor.oxfordjournals.org/Downloaded from

Spilker ME, Sprenger T, Valet M, Henriksen G, Wagner K, Wester HJ,
Toelle TR, Boecker H. 2004. Quantification of [18F]diprenorphine
kinetics in the human brain with compartmental and non-
compartmental modeling approaches. Neuroimage. 22:1523--1533.
Sprenger T, Berthele A, Platzer S, Boecker H, Tolle TR. 2005. What
to learn from in vivo opioidergic brain imaging? Eur J Pain.
9:117--121.
Sprenger T, Valet M, Boecker H, Henriksen G, Spilker ME, Willoch F,
Wagner KJ, Wester HJ, Tolle TR. 2006. Opioidergic activation in the
medial pain system after heat pain. Pain. 122:63--67.
Stern RA, Arruda JE, Hooper CR, Wolfner GW, Morey CE. 1997. Visual
analogue mood scales to measure internal mood state in aphasic
patients: description and initial validity evidence. Aphasiology.
11:59--71.
Talairach J, Tournoux P. 1988. Co-planar stereotaxic atlas of the human
brain: three-dimensional proportional system: an approach to
cerebral imaging. New York: Thieme.
Tendzegolskis Z, Viru A, Orlova E. 1991. Exercise-induced changes of
endorphin contents in hypothalamus, hypophysis, adrenals and
blood plasma. Int J Sports Med. 12:495--497.
Wagemaker H, Goldstein L. 1980. The runner’s high. J Sports Med Phys
Fitness. 20:227--229.
Wang GJ, Volkow ND, Fowler JS, Franceschi D, Logan J, Pappas NR,
Wong CT, Netusil N. 2000. PET studies of the effects of aerobic exercise
on human striatal dopamine release. J Nucl Med. 41:135 2--1356.
Wester HJ, Willoch F, Tolle TR, Munz F, Herz M, Oye I, Schadrack J,
Schwaiger M, Bartenstein P. 2000. 6-O-(2-[18F]fluoroethyl)-6-O-
desmethyldiprenorphine ([18F]DPN):synthesis,biologicevaluation,
and comparison with [11C]DPN in humans. J Nucl Med. 41:1279--1286.
Wildmann J, Kruger A, Schmole M, Niemann J, Matthaei H. 1986.
Increase of circulating beta-endorphin-like immunoreactivity cor-
relates with the change in feeling of pleasantness after running. Life
Sci. 38:997--1003.
Winston JS, O’Doherty J, Dolan RJ. 2003. Common and distinct neural
responses during direct and incidental processing of multiple facial
emotions. Neuroimage. 20:84--97.
Zubieta JK, Ketter TA, Bueller JA, Xu Y, Kilbourn MR, Young EA,
Koeppe RA. 2003. Regulation of human affective responses by
anterior cingulate and limbic mu-opioid neurotransmission. Arch
Gen Psychiatry. 60:1145--1153.
Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM,
Meyer CR, Koeppe RA, Stohler CS. 2001. Regional mu opioid
receptor regulation of sensory and affective dimensions of pain.
Science. 293:311--315.
Cerebral Cortex November 2008, V 18 N 11 2531
by guest on June 6, 2013http://cercor.oxfordjournals.org/Downloaded from