Clinical Science (1984)67, 483-491
483
The role of opioid peptides in the hormonal responses to
acute exercise in man
A. GROSSMAN, P. BOULOUX, P. PRICE, P. L. D R U R Y , K . S . L. LAM,
T. T U R N E R , J . THOMAS, G . M . BESSER A N D J . SUTTON*
Departments of Endocrinology and Psychological Medicine, St Bartholomew’s Hospital, London, and
*Department of Medicine, McMaster University, Hamilton, Ontario, Canada
(Received 23 November 1983; accepted 17 April 1984)
Summary
1. Opioid involvement in the physiological and
hormonal responses to acute exercise was investigated in six normal male subjects. Each was
exercised to 40% (mild exercise) and 80% (severe
exercise) of his previously determined maximal
oxygen consumption on two occasions, with
and without an infusion of high-dose naloxone.
The exercise task was a bicycle ergometer; mild
and severe exercise were performed for 20min
each, followed by a recovery period.
2. Exercise produced the expected increases in
heart rate, blood pressure, ventilation, tidal
volume, respiratory rate, oxygen consumption and
carbon dioxide production. After severe exercise,
naloxone infusion increased ventilation from
94.8 4.9 litres/min to 105.7 k 5.0 litres/min (P<
0.05), but had no effect on any of the other
physiolo.gica1 variables.
3. Exercise-induced changes in several hormones and metabolites were noted, including
elevations in circulating lactate, growth hormone
(GH), prolactin, cortisol, luteinizing hormone
(LH), follicle stimulating hormone (FSH),
adrenaline, noradrenaline, plasma renin activity
(PRA) and aldosterone. There was no change in
plasma met-enkephalin. Naloxone infusion produced the expected increases in LH and cortisol,
but also significantly enhanced the elevations in
prolactin, adrenaline, noradrenaline, plasma renin
activity and aldosterone (P<O.O5).
*
Correspondence: Dr A. Grossman, Department
of Endocrinology, St Bartholomew’s Hospital,
London EClA 7BE.
4. Psychological questionnaires revealed minor
mood changes after exercise, but no evidence was
found for the suggested ‘high’ or euphoria of
exercise. Effort was perceived as greater during the
naloxone infusion than the saline infusion in every
subject.
5. We conclude that endogenous opioids may
be important in the control of ventilation and the
perception of effort at high levels of power
output, and may modulate the responses of circulating catecholamines and the renin-aldosterone
system to acute physical stress.
Key words: catecholamines, exercise, opiates.
Introduction
The hormonal responses to acute exercise and
their modification by physical training have
recently been the subject of considerable study
[l-51. Furthermore, the topic has been the basis
of several reviews [6-lo]. Recent studies have
demonstrated that concentrations of circulating
@endorphin increase in response to exercise
[ll-131. It has been suggested that changes in the
endogenous opioid peptide secretion may be
responsible for certain of the psychological and
hormonal alterations associated with exercise
[14]. The opiate antagonist, naloxone, has been
shown to block exercise-induced release of prolactin and growth hormone (GH) in one study of
professional athletes [ 151, but other workers have
been unable to demonstrate an effect of either
low-dose or high-dose naloxone on exerciseinduced hormonal changes [16, 171. The purpose
484
A . Grossman et al.
of the present study was to re-evaluate the importance of opioid peptides in the hormonal and
physiological responses to low- and high-intensity
exercise by conducting a rigorously controlled
double-blind cross-over and randomized study,
using an infusion of high-dose naloxone before and
during exercise in normal subjects.
Methods
Six normal male subjects (age range 18-31 years)
were studied. Each was free of any disease and on
no medication at the time of the study. The
subjects were active, but were not undergoing
regular training. In a preliminary experiment, the
subjects performed a progressive exercise test to
exhaustion on a cycle ergometer to determine
their maximum power outputs [18], and allow
selection of appropriate exercise intensities for the
hormonal studies.
Each subject was then tested on two occasions
and attended the laboratory after an overnight
fast. At 08.30 hours, an indwelling intravenous
cannula was inserted into each forearm, after
which the subject rested supine for 30 min. Beginning 5 min before exercise, an intravenous
infusion of either naloxone or an equal volume of
saline was commenced. Naloxone (Narcan, Du
Pont (UK) Ltd, Stevenage, Herts, U.K.) was given
as a bolus of 8 mg followed by an infusion of
5.6 mg/h, terminating at the end of high-intensity
exercise, a total dose of 12.2 mg. Saline and
naloxone studies were carried out in a randomized
double-blind cross-over design and a minimum of
1 week separated the studies on each individual.
Exercise and cardiorespiratory measurements
Exercise was performed on an electrically
braked cycle ergometer. The subjects breathed
through a low-resistance one-way valve connected
to an appropriately calibrated P.K. Morgan
measurement system. The measurements obtained
were ventilation, tidal volume, frequency of
breathing oxygen consumption ( VO,), carbon
dioxide production (Vco,) and respiratory
exchange ratio ( R ) . Heart rate and blood pressure
were determined by an experienced observer who
auscultated over the precordium for heart rate and
measured blood pressure (Phases 1 and IV) with a
sphygmomanometer. After the collection of basal
samples, the subject exercised at 40% of his
previously determined maximum power output
for 20 min (mild exercise), followed by a further
20min at 80% of this maximum power output
(severe exercise). He then rested supine for 50 min
(recovery period).
Hormonal and metabolic measurements
Venous blood was collected at intervals before,
during and after exercise, and was immEdiately
separated at 4°C and flash-frozen at -20 C until
assayed. The following hormones were measured:
prolactin, growth hormone (GH), luteinizing
hormone (LH), follicle stimulating hormone
(FSH), thyroid stimulating hormone (TSH),
cortisol, testosterone, aldosterone, plasma renin
activity (PRA), adrenaline, noradrenaline and metenkephalin. Glucose and lactate were also
measured.
All peptide and steroid hormones were assayed
by radioimmunoassay ; standards for prolactin,
GH, LH, FSH and TSH were IRP 75/504, MRC
66/217, MRC 68/40, MRC 69/104 and MRC
68/38 respectively. Radioimmunoassay was also
used for cortisol (Corning Medical Supplies,
Halstead, Essex, U.K.), aldosterone [19] and
testosterone. PRA was measured by a modification of the radioimmunoassay of Haber et al.
[20] at pH 7.4. Catecholamines were separated by
high-performance liquid chromatography and
assayed by electrochemical detection [21]. Metenkephalin was measured by the method of
Clement-Jones er al. [22]. Blood glucose was
measured by the glucose oxidase technique, and
lactate by spectrophotometry. All samples for a
given subject were measured in one assay to avoid
interassay variance; the coefficient of variation
was <5% for all measurements except catecholamines (7%).
Psychological tests
A psychological mood questionnaire was
administered in the resting state immediately
before exercise, immediately after the exercise,
and at the end of the recovery period. On each
occasion, the subjects completed an 18-item visual
analogue scale relating to mood and affect [23].
Statistical analysis
The effect of exercise on cardiorespiratory
variables was subjected to analysis of variance to
investigate the effects of exercise, naloxone
treatment, and order of treatments. Logarithmic
transformation of all variables other than GH
produced a normal distribution; that for GH
deviated slightly from normality, but no other
transformation was more effective. In all circumstances, the difference was regarded as significant
if P < 0.05. The psychological tests were examined
as mean changes from basal levels, and between
naloxone and saline. These were compared by
Opioids and exercise
means of the Wilcoxon matched-pairs signedranks test [24].
Data are given as mean f SEM.
Results
The preliminary progressive exercise test revealed
maximum power outputs between 210W and
270 W, in the normal range expected for adult
active but untrained males. Power outputs selected
for the steady-state exercise tests were: 40%,
98 W and 80%, 196 W. Exercise resulted in highly
significant in.creases in heart rate, blood pressure,
ventilation, Vo, and Vco, (Tables 1 and 2). There
was no difference between the naloxone and the
control studies for any of the variables except
ventilation (Table 2), which was increased following naloxone at maximum exercise (105.7 f 5.0
litres/min vs 94.8 f 4.9 litres/min).
infusion, between the naloxone and saline studies
for any hormone, glucose or lactate. There was a
small but significant trend for serum LH, FSH,
PRA and serum aldosterone to be higher on the
second test occasion.
Prolactin. Serum prolactin rose during exercise
from a basal level of 201 40 m-units/l to a peak
of 449 174 m-units/l at 50 min; during naloxone
infusion, serum prolactin rose from 198 f 42
m-unit$ to 590 201 m-unit$. There was a
significant effect of exercise, and the difference
between saline and naloxone in.fusions was also
significant.
Growth hormone. There was a highly significant increase in GH with exercise (P < 0.001), in
both the control and naloxone studies to a peak at
45 min of 73 10 m-units/l (control) vs 101
17 m-units/l (naloxone). There was no significant
effect of naloxone.
Luteinizing hormone/follicle stimulating hormoneltestosterone. There were small but significant rises in serum LH, FSH and testosterone after
exercise in the control study; naloxone significantly increased the LH response to exercise. In
*
+_
+_
Basal concentrations of all the hormones were
in the expected range and there were no significant differences in basal levels, before naloxone
*
*
+
Hormonal and metabolic variables (Table 3)
TABLE 1.
485
Basal and peak values of physiological variables during mild exercise following the infusion o f saline or high-dose naloxone
Naloxone
Saline
Heart rate (beatslmin)
Mean blood pressure (mmHg)
Respiratory rate (min-')
Ventilation (l/min)
Tidal volume (litres)
yo, (ml/min)
VCO, (ml/min)
R
TABLE
Basal
Peak
Basal
Peak
72 i 12
98 i4
13.4 f 1.3
11 io.9
0.9 io.l
332i11
292 i 20
0.88
119i5
102 24
22.1 i 1.3
39.9 i 1.8
1.8 ~0.1
1596 i 67
1401 i 54
0.88
60i3
97 i2
14.3i 1.9
10.7 i0.7
0.8iO.l
340 A 12
276 i 18
0.82
119i5
106i3
23.6k1.7
42.4 i3.1
1.8i0.1
1555 i68
1402 i51
0.87
2. Basal and peak values of physiological variables during intense exercise
following the infusion of saline or high-dose naloxone
Naloxone
Saline
~
~~
Basal
Peak
Basal
Peak
72i12
98 i4
13.4 i 1.3
11 io.9
0.9 io.1
332 f 11
292 i 20
0.88
180 f 5
117 f 8
36.6 i2.1
94.8 f4.9
2.6 i0.2
2943 i 148
2910 i 134
0.98
60i3
97i2
14.3 i 1.9
10.7 i0.7
0.8 kO.1
340 i 12
276 i 18
0.82
184 i5
111 f 2
40.6t4.8
105.7 i5
2.1 i0.2
2995 i 138
2972 f 139
0.99
~~
Heart rate (beatslmin)
Mean blood pressure (mmHg)
Respiratory rate (min-')
Ventilation (l/min)
Tidal volume (litres)
Y O , (ml/min)
VCO (ml/min)
R
A. Grossman et al.
486
TABLE 3. Basal and peak values of circulating hormones during exercise after the
infusion o f saline or high-dose naloxone
Saline
Hormone
~
Naloxone
Basal
Peak
Basal
Peak
201 * 40
20* 13
4.6 0.3
2.8* 0.8
2.0* 0.3
18.8* 1.8
425* 52
0.27* 0.07
509* 70
0.12* 0.02
0.75 * 0.1
74* 14
449* 174
72.6* 9.6
7 . 2 i 1.5
3.6 * 0.9
1.4*0.3*
24.2.t 3.8
634* 94
2.23+0.68
1610* 264
1.17* 0.2
10.3 * 0.8
98+ 20
198* 4 2
11.2f 6.6
5.6 f. 0.7
2.9* 1
2.1 * 0.3
17.0* 1.6
401 f 83
0.39f 0.09
542* 53
0.12*0.01
0.89 * 0.2
88* 17
590* 201
101 f 16.8
11.4r2
4.2.t 1.4
1.1 * 0.2*
22.6f 1.5
876* 88
3.51 0.59
2155* 386
2.25 * 0.3
13.lr 1
90f 22
~
Prolactin (m-u nits/l)
GH (m-units/l)
LH (units/l)
FSH (units/l)
TSH (munits/l)
Testosterone (nmol/l)
Cortisol (nmol/l)
PRA (pmol of ANG I h-' ml-')
Aldosterone (pmol/l)
Adrenaline (nmol/l)
Noradrenaline (nmol/l)
Met-enkephalin (pmol/l)
*
*
* Peak fall.
40% 80%
40% 80%
I
vo2
-30,
d
h
I.
E
25001 ('
I
-
1500 1000 500 -
4 20000
I
-30
I
I
0
20 40 60
Time (min)
90
-30
0
20 40 60
Time (min)
90
FIG. 1 . Changes in plasma renin activity (a) and serum aldosterone ( b ) during exercise
after saline ( 0 - - - - 0 ) or naloxone (-)
infusion.
addition, there was an order effect in that serum
LH and FSH were significantly higher during the
second study day.
Thyroid stimulating hormone. TSH slightly
decreased following exercise, with no difference
between the exercise responses in the control or
naloxone studies.
Cortisol A small increase in cortisol occurred
after exercise that just attained significance; there
was a highly significant response to naloxone.
Plasma renin activityfaldosterone (Fig. 1).
Exercise resulted in a significant increase in PRA
from 0.27k0.07 to 2.23k0.68 pmol of ANG I
h-' ml-', which was further significantly enhanced by naloxone (0.39 f 0.09 to 3.5 1 f 0.59
pmol of ANG I h-' ml-').
Serum aldosterone concentration signficantly
increased from 509 f 70 to 1610 f 264 pmol/l, a
response which was further enhanced significantly
by naloxone infusion (542 f 53 to 2155 f 386
pmol/l).
Plasma catecholamines (Fig. 2). There was a
highly significant response in plasma noradrenaline
from 0.75 f 0.1 nmol/l to 10.3 f 0.8 nmol/l and in
plasma adrenaline from 0.1 2 f0.02 nmol/l to
1.17 f 0.2 nmol/l. Naloxone augmented the
increase in noradrenaline response to exercise
from 9.6 f0.7 nmol/l to 12.2 k 1.0 nmol/l. The
plasma adrenaline response was also significantly
augmented by naloxone (1.04k0.15 nmol/l to
2.12 f 0.3 nmol/l).
Plasma met-enkephalin (Fig. 3). There was no
change in circulating met-enkephalin in response
to exercise in either study, nor was there a
difference with the naloxone infusion. All values
remained within the normal range (<200 pmol/l).
-
Opioids and exercise
40% 80%
40% 80%
I
vo,
Go,
(a)
5
c
3
3
j
487
2.0
-
Y
z
i,
a
l.O
-
6
0-
0-
Mood questionnaire
At the end of severe exercise, there were small
but significant increases in items for ‘gregariousness’, ‘clumsiness’ and ‘excitement’, and a marked
increase on the scale ‘feebleness’. These abated
during the recovery period and were unchanged in
the presence of naloxone. However, at the end of
the recovery period, scales for ‘lethargy’ and
‘drowsiness’ were significantly increased by
naloxone. There was no evidence for exerciseinduced euphoria under either experimental
condition.
In addition to the mood questionnaire, the
subjects were asked to identify which study was
more difficult. In all six subjects, naloxone was
perceived as the more difficult study, involving
greater effort.
!+-+
.’
-1
1
L
I
I
0
20
I
I
40
60
Time (min)
I
90
FIG. 3. Changes in plasma met-enkephalin during
exercise after saline (*- - - -e) or naloxone
(M)
infusion.
Glucose/lactate. There was no significant
change in blood glucose with exercise, and no
effect of naloxone was seen (data not shown).
The expected rise in blood lactate occurred
during exercise and was greater with the highintensity exercise; however, there was no
difference between the naloxone and control
studies.
Discussion
In this exercise study at two levels of power output, expected responses were observed in the
cardiovascular, ventilatory,
metabolic and
hormonal variables. High-dose naloxone enhanced
many of these responses including ventilation and
several of the hormonal variables, thus implicating
chronic opioid inhibition in the regulation of
ventilation and in the release of those hormones.
Cardiovascularand ventilatory responses
Heart rate and blood pressure increased at each
level of work, being greater at the higher level of
488
A . Grossman et al
work. The heart rate approached the age-predicted
maximum for the individuals when they exercised
at 80% of their maximum power output for
20 min. The response of heart rate and blood
pressure was unaltered with the infusion of
naloxone. Ventilation, tidal volume and frequency
were increased at both levels of. work, being
greater at the higher level, as were Vo, and VCO,.
The respiratory exchange ratio ( R ) was also
higher at the higher intensity of work, consistent
with a greater use of carbohydrate as energy
substrate. Of the ventilatory variables, ventilation
was significantly enhanced by naloxone. Although
previous studies in man have not demonstrated an
effect of naloxone on spontaneous or hypoxiainduced increases in ventilation [25], there are a
number of studies which suggest that endogenous
opioids may depress ventilation [26-291. Nevertheless, as endogenous opioids and opioid
receptors are found in the brain stem of a number
of mammals [30], and an enkephalin-like peptide
has been found in the carotid body type 1 glomus
cells [31, 321, it would not be surprising if the
endogenous opioid system might play a role in
ventilatory regulation by CO, and hypoxia. This
has been demonstrated as occurring in the cat in
elegant studies by Pokorski & Lahiri [33]. As the
ventilatory responses to exercise, CO, and hypoxia
are similar in humans (reviewed by Sutton &
Jones [34]), the findings in the present study of
an augmented ventilatory response with high-dose
naloxone is consistent with a physiological role for
the endogenous opioid system in ventilatory
regulation in humans.
Hormonal responses
Growth hormone and prolactin. Exercise resulted in a highly significant elevation in serum
GH in all subjects, confirming the efficacy of acute
high-intensity exercise in stimulating GH secretion
[ l , 351; however, there was only a small elevation
in serum prolactin. The GH change was not altered
by naloxone infusion; serum prolactin release was
slightly enhanced. These data are consistent with
those of Mayer et al. [16] in untrained subjects
and Sutton et al. [17] in athletes, and suggest that
the release of prolactin and GH by exercise, per se,
is independent of endogenous opioid peptides.
However, these findings are in apparent conflict
with the report of Moretti et al. [15] who found
that the exercise increases in both serum prolactin
and GH, when professional athletes exercised at
high intensity, were naloxone-reversible. Furthermore, the subjects studied by Moretti et al. [15]
were more highly trained than those of Sutton
et al. [17], and training as such has been well
demonstrated to alter the hormonal responses to
exercise [I-31. More recently, Carr et al. [12]
have demonstrated an important effect of training
on P-endorphin and prolactin release in female
subjects, and Boyden et al. [36] have shown that
the prolactin response to thyrotrophin releasing
hormone (TRH) increases during endurance
training in women.
Thyroid stimulating hormone. TSH decreased
slightly following exercise, but no effect of
naloxone was seen. Previous studies have demonstrated that intravenous naloxone will result in a
decrease in TSH in the resting state [37,38].
Luteinizing hormone, follicle stimulating hormone and testosterone. Exercise increased serum
concentrations of LH, FSH and testosterone, but
the changes were relatively slight. Changes in
serum testosterone have previously been reported,
without any change in serum LH, possibly due to
the small magnitude of such changes [ l , 39, 401.
Opiate involvement in gonadotropin release has
been well documented (411.
Serum cortisol. Previous studies have demonstrated that sufficiently intense exercise will
enhance adrenocorticotrophic hormone (ACTH)
and cortisol release, and our findings are compatible with these [ 1,421. The effect of high doses
of naloxone on serum cortisol are well established
[43I.
Plasma catecholamines. Plasma noradrenaline
and adrenaline increased significantly during
exercise, the response being greater with highintensity exercise. The influence of exercise on
both catecholamines was significantly enhanced by
naloxone infusion, and this was especially true
for adrenaline. Although the exercise-induced
increase of catecholamines is well known, the role
of opioids in the control of catecholamine secretion is controversial. Estilo & Cottrell [44] showed
that basal concentrations of noradrenaline and
adrenaline were unaffected by low-dose naloxone
(0.6 mg), whereas Naber et al. [45] showed that
high-dose naloxone (8 mg) increased plasma 3methoxy-4-hydroxyphenylglycol (MHPG), a major
metabolite of noradrenaline. Furthermore, we
have shown that an analogue of met-enkephalin
decreased circulating adrenaline and noradrenaline
basally, and suppressed their elevations in response
to insulin-induced hypoglycaemia [46, 471. Thus,
on balance, these findings would support a tonic
opioid inhibition of catecholamine secretion.
Plasma renin activity and serum aldosterone.
Both PRA and serum aldosterone increased significantly in exercise, an effect enhanced in both by
naloxone infusion. Lightman [48] showed a
tendency for PRA and aldosterone to be increased
by high-dose naloxone, although the changes did
Opioids and exercise
not reach statistical significance. It seems probable
that there is a direct opiate modulation of the
sympathetic nervous system and the adrenal
medulla which, in turn, regulates the renin-aldosterone axis. Nevertheless, direct effects of
endogenous opioids on renin secretion and on the
adrenal cortex could also explain the present
findings, as suggested by several other studies
[49-511.
Plasma met-enkephalin. No change was noted in
circulating met-enkephalin concentration during
exercise either in the control study or the
naloxone study. As met-enkephalin is co-stored
and co-released with catecholamines within the
adrenal medulla, this may seem surprising in the
light of the highly significant changes in plasma
adrenaline. However, previous studies have shown
that the adrenal medulla is not the only source of
met-enkephalin, as normal plasma concentrations
have been demonstrated in adrenalectomized
subjects or during insulin-induced hypoglycaemia
[ 5 2 ] . This suggests that a major fraction of the
circulating met-enkephalin is derived from other
sources and changes in met-enkephalin originating
from the adrenal medulla may change the circulating level only marginally.
Psychological assessment
The psychological changes induced by exercise
were scored for gregariousness, clumsiness and
excitement. It was interesting to note that there
was no increase in feelings of well-being or
euphoria demonstrated in either circumstance.
Thus, under the present circumstances, exercise
did not result in the so-called 'high', nor was
this aspect of mood altered by naloxone. While
there have been many reports in the popular
press and running magazines of exercise-induced
mood changes and addictive-Like states, it is
difficult to find scientific support for such statements [53,54].
The increased perception of effort with
naloxone is of some interest. Many studies attest
to the relative lack of psychological change
induced by this dose of naloxone under basal
conditions, and it is possible that during exercise
the perception of fatigue is modulated by an
increase in endogenous opioid peptides. It is also
possible that this change in perception is
responsible for the increased release of prolactin
seen under naloxone infusion. The relative
enhancement of renin, aldosterone and catecholamine release during naloxone is of such a magnitude as to render it unlikely that they are due to
changes in effort perception alone. In addition, a
recent report has demonstrated an increase in
489
plasma catecholamines after naloxone administration in another situation where basal levels are
elevated, namely in a patient with a phaeochromocytoma [%I, and the catecholamine response to
hypoglycaemia is also enhanced by naloxone
infusion [47]. Furthermore, the noradrenaline
response to tilt is antagonized by an analogue of
met-enkephalin [56].
In conclusion, our studies demonstrate that the
exercise-induced release of prolactin, PRA, aldosterone, adrenaline and noradrenaline are enhanced by naloxone infusion. The mechanism and
site of action for these changes remains undetermined at present.
Acknowledgments
We gratefully acknowledge the assistance of Professor L. H. Rees, Professor K. G. M. M. Alberti,
Dr W. A. Stubbs and L. Perry in carrying out
many of the assays, the help of A. Cobley in
physiological measurements, and the use of the
laboratory facilities offered by Professor R. H. T.
Edwards. We thank Miss Fenella Moore for
secretarial assistance.
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