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Beta-endorphin modulates the acute response

to a social conflict in male mice but does not
play a role in stress-induced changes in sleep.
ARTICLE in BRAIN RESEARCH AUGUST 2003
Impact Factor: 2.83 DOI: 10.1016/S0006-8993(03)02805-1 Source: PubMed

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Research report

b-Endorphin modulates the acute response to a social conflict in male

mice but does not play a role in stress-induced changes in sleep
Lobke M. Vaanholt, Fred W. Turek, Peter Meerlo*
Department of Neurobiology and Physiology, Northwestern University, Evanston, USA
Accepted 9 April 2003

Abstract
b-Endorphin is an endogenous opioid peptide that is released during stress and has been associated with many physiological functions.
In this experiment b-endorphin deficient mice were used to study the role of endorphins in the acute physiological and behavioral
responses to a social conflict, as well as their role in social stress-induced changes in sleep. Adult male b-endorphin deficient and wild
type mice were subjected to the stress of a 1 h social conflict with an aggressive dominant conspecific. After the conflict, the b-endorphin
deficient mice had higher corticosterone levels but the peak increase in body temperature was not different from that in wild type animals.
In fact, body temperature returned to baseline levels faster in the b-endorphin deficient mice. During their interaction with the aggressive
conspecific several of the b-endorphin deficient mice showed clear signs of counter aggression whereas this was not seen in any of the
wild type mice. Overall, the b-endorphin deficient mice and wild type mice had fairly similar sleep patterns under baseline conditions and
also showed similar amounts of NREM sleep, REM sleep and EEG slow-wave energy after the social conflict. In addition, no differences
were found in the sleep patterns of mice that showed counter aggression and mice that did not. In conclusion, the results suggest that
b-endorphin modulates the acute endocrine, thermoregulatory and behavioral response to a social conflict but the data do not support a
major role for b-endorphin in the regulation of sleep or social stress-induced alterations in sleep.
2003 Elsevier Science B.V. All rights reserved.
Theme: Neural basis of behavior
Topic: Stress
Keywords: Social conflict; Aggression; Opioid; Glucocorticocoid; Body temperature; REM sleep

1. Introduction
b-Endorphin is an endogenous opioid that acts as a
neuropeptide within the central nervous system and functions as a hormone in the periphery upon release in the
blood stream [1,6]. In the brain, b-endorphin producing
cells are found in the hypothalamic arcuate nucleus and the
caudal nucleus tractus solitarius, which together have
extensive projections throughout the brain [15]. The neurons of the arcuate nucleus innervate other hypothalamic
regions, structures of the limbic system, and various areas
in the brain stem. Also the nucleus tractus solitarius
*Corresponding author. Department of Molecular Neurobiology, University of Groningen, P.O. Box 14, 9750 AA Haren, The Netherlands.
Tel.: 131-50-363-2334; fax: 131-50-363-2331.
E-mail address: p.meerlo@biol.rug.nl (P. Meerlo).

exhibits projections within the brainstem to the lateral

reticular nucleus. In addition to these central systems,
b-endorphin producing cells are found in the anterior and
intermediate lobes of the pituitary gland, from where
endorphins are released into the circulation [15].
b-Endorphin has various functions but is especially well
known as an analgesic compound and a factor that
modulates the physiological and behavioral response to
stressors [14,22,24,29,32, for reviews see 1,6,18,25]. Although few studies have addressed this issue, stress-induced release of b-endorphin might also affect subsequent
sleep. In agreement with this, human beings receiving
opioids often feel sleepy while the rapid eye-movement
(REM) phase of their sleep is actually inhibited [5]. In
cats, microinjections of b-endorphin and other opioids in
the brain have variable effects on slow wave sleep or
non-rapid eye-movement (NREM) sleep, depending on the

0006-8993 / 03 / $ see front matter 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016 / S0006-8993(03)02805-1

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L.M. Vaanholt et al. / Brain Research 978 (2003) 169176

brain area and the receptor types that are activated, but a
number of studies report increased signs of NREM sleep
[9,27]. In cats, similar to opioid effects in humans, bendorphin may cause a strong reduction in REM sleep
[16].
Interestingly, some of the reported effects of exogenous
b-endorphin administration mimic the effects of social
defeat stress on sleep in rodents. In particular, mice rapidly
overcome the arousal that is induced by a social conflict
and show an increase in NREM sleep afterwards, while
REM sleep, on the other hand, is strongly suppressed [20].
It is known that a social conflict in rodents activates central
and peripheral opioid systems and causes an increase in
b-endorphin levels [8,13,22,30,31], particularly in defeated
animals as compared to dominants [8,13]. In the present
study, experiments were performed with b-endorphin
deficient mice to determine the role of endorphins in the
physiological and behavioral response to a social conflict
and, in particular, the role of b-endorphins in sleep and
social stress-induced changes in sleep. If b-endorphins
would facilitate NREM sleep and inhibit REM sleep after
social defeat stress, one would expect a prolonged period
of wakefulness but a less pronounced decrease in REM
sleep after a conflict in b-endorphin deficient mice.

2. Materials and methods

cycle with lights on from 9:00 to 21:00. Food and water

were provided ad libitum.

2.2. Experiment 1: body weight, aggression and

corticosterone
In the first experiment, 14 wildtype and 16 b-endorphin
deficient mice were subjected to a social interaction with
an aggressive male. The aggressive males were animals of
the same strain (C57BL / 6J) that were older and heavier
than the experimental animals. They had been trained to
fight and protect their territory by housing them with a
female and regularly exposing them to young males the
week prior to the experiment [19,20].
The experimental animals were placed in the home cage
of the aggressor for a period of 1 h. The interaction took
place during the 6th hour of the light phase, conforming to
our previous study in mice [20]. Prior to the conflict, body
weights of the experimental animals were measured.
During the conflict, the number of clinches was recorded
and, since some of the experimental animals displayed
counter aggression towards the resident male, we also kept
a record of this. Afterwards, the experimental animals were
decapitated and their trunk blood was collected in prechilled (0 8C) tubes with EDTA as anticoagulant. The
blood was centrifuged at 4 8C for 15 min at 2600 g and the
supernatant was stored at 280 8C for later analysis.
Corticosterone levels were determined by radioimmunoassay (ICN Biomedicals, Costa Mesa, USA).

2.1. Animals and housing

2.3. Experiment 2: body temperature and sleep
The b-endorphin deficient mice were originally produced by introducing a point mutation into the proopiomelanocortin gene so that it translates to a truncated
prohormone lacking the entire C-terminal amino acid
region encoding b-endorphin [28]. b-Endorphin deficient
mice have a normal birth weight and development into
adulthood. However, after the onset of puberty they attain
1015% more weight than wild type mice. As expected,
opioid function is reduced as reflected in a decrease in
opioid-induced analgesia [29]. Otherwise, stress reactivity
and overt behavior appears to be normal in adult bendorphin deficient mice [29].
For the present study, male and female homozygous
wild type C57BL / 6J and b-endorphin deficient mice (stock
name C57BL / 6-Pomc tm1Low) were obtained from Jackson
Laboratory (Bar Harbor, ME, USA). With these mice a
breeding colony was started. Homozygous b-endorphin
deficient mice were crossed with homozygous wildtypes to
obtain heterozygous offspring. This offspring was crossed
and the second generation was then genotyped and used in
the experiments described hereafter. In all experiments
34-month-old males were used. The animals were individually housed from about 2 weeks before the start of
the experiment and were kept under a 12 h-light12 h-dark

For sleep recordings, 14 wildtype and 15 b-endorphin

deficient mice were implanted with permanent electrodes
to record cortical EEG and neck muscle EMG as described
previously [20,21]. In brief, two screws in the skull served
as EEG electrodes, one placed above the right hemisphere,
2 mm from the midline and 1 mm anterior of bregma, and
one placed on the left hemisphere, 3 mm from the midline
and 1 mm anterior of lambda. Two insulated stainless-steel
wires served as EMG electrodes and were inserted under
the neck muscles. The EEG and EMG electrodes were
attached to a connector that was cemented on the skull
with dental acrylic. In addition to the head implant, a
transponder for body temperature measurements was
placed in the abdominal cavity (Model PDT4000; Minimitter, Sunriver, Oregon, USA). After at least 2 weeks of
recovery from surgery, the mice were hooked up to the
recording equipment via a recording cable and a swivel,
which allowed free movement throughout the cage. After 3
days of habituation to the recording tether, EEG and EMG
signals were recorded and fed into an amplifier (Grass
model 12; Grass Instrument Division, Astro-med, West
Warwick, RI, USA). The EEG signal was amplified 10 000
times, high-pass filtered at 1 Hz (26 dB, 6 dB / octave) and

L.M. Vaanholt et al. / Brain Research 978 (2003) 169176

low-pass filtered at 30 Hz (26 dB, 6 dB / octave). The

EMG signal was amplified 5000 times, high-pass filtered at
3 Hz and low-pass filtered at 100 Hz. The signals were
then converted to digital format and stored at 102.4 Hz
resolution. The signals were collected on an IBM computer
system with specialized software for acquiring and processing sleep data in rodents (Multisleep; Actimetrics,
Evanston, IL, USA).
Baseline recordings were made from the beginning of
the light phase until the end of the dark phase. During the
6th hour of the light phase of the following (experimental)
day animals were subjected to a 1-h social conflict as
described above. During this conflict animals remained
attached to the recording system. EEG, EMG and body
temperature were recorded for an 18-h recovery period,
until the end of the following dark phase.
By visual inspection of the EEG and EMG signals, 10-s
epochs were classified as wakefulness, NREM sleep or
REM sleep [20]. In addition, the EEG signal was subjected
to spectral analysis by fast Fourier transformation and, for
all NREM epochs, the EEG deltapower was calculated,
that is, the spectral density in the delta or slow wave range
(14 Hz). The amount and amplitude of slow waves in the
EEG is considered to be an indication of NREM sleep
intensity [3,7,12]. To correct for interindividual differences
in the strength of the EEG signal, the delta power values of
all animals were normalized by expressing them relative to
their average NREM sleep delta power during the 24-h
baseline recording. The accumulation of NREM sleep delta
power was calculated per 6-h interval and expressed as
percentage of the total 24 h NREM sleep deltapower
during baseline [20]. The normalized accumulated deltapower is referred to as slow wave energy (SWE). Body
temperature was also measured every 10 s. For statistical
analysis, average temperature was calculated for 6- and
12-h blocks. The deviation from baseline was calculated
for the first 6 h after the conflict.

171

3. Results

3.1. Experiment 1: body weight, aggression and

corticosterone
At an adult age of 4 months, the b-endorphin deficient
mice were about 10% heavier than wild type mice
(27.760.5 g versus 30.960.4 g, respectively; t54.88;
P,0.001). When the mice were transferred to the cage of
an aggressive dominant conspecific, all experimental animals were readily attacked. The number of clinches the
experimental animals were involved in did not differ
between wildtypes and b-endorphin deficient mice (Fig.
1). However, whereas all of the wild type mice were
submissive, as indicated by freezing or fleeing, eight out of
sixteen b-endorphin deficient mice initially showed clear
signs of counter aggression, including tail rattling, initia-

2.4. Statistics
For statistical analysis of body weight and corticosterone
levels, two-sample t-tests were applied. Also the average
24- and 12-h light / dark values of body temperature during
baseline were analyzed with two-sample t-tests. In addition, for 1- and 6-h values of body temperature and sleep
data, repeated measures ANOVA was performed with a
factor genotype (wildtype vs. b-endorphin deficient) and a
factor time (1-h blocks and 6-h blocks). For body temperature and sleep after the conflict, the deviations from the
corresponding baseline values were calculated. When
ANOVA revealed an overall effect of genotype or a
genotype3time interaction, separate blocks were tested
with two-sample t-test. Within each genotype, data collected on the experimental day were compared with
corresponding baseline values using a paired t-test.

Fig. 1. Number of clinches during a 1-h social conflict with an aggressive

conspecific (top) and the corticosterone level at the end of the conflict
(bottom) in wild type mice (n514, grey bars) and b-endorphin deficient
mice (n516, black bars). The figure shows the average values (6S.E.M.).
Significant difference between genotypes: *, P,0.005.

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L.M. Vaanholt et al. / Brain Research 978 (2003) 169176

tion of clinches, and chasing the resident cage owner. The

outcome of the fights in which experimental animals
counter-reacted was not always clear, but at the end of the
1-h interaction most of them displayed the typical freezing
and avoidance behavior suggesting submission. The occurrence of counter aggression in the b-endorphin deficient
mice was not related to their body weight. When a
comparison was made within the b-endorphin deficient
group between animals that showed counter aggression
during the conflict and the ones that did not, contrary to
what one might expect, the mice that showed counter
aggression were slightly lighter than animals that did not
show counter aggression (P50.099).
At the end of the 1-h social conflict, the corticosterone
levels in the b-endorphin deficient mice were on average
slightly but significantly higher compared to the levels in
the wild type mice (Fig. 1; t52.29; P50.027). Importantly, within the group of b-endorphin deficient mice, the
corticosterone levels did not differ between the animals
that showed counter aggression and the ones that did not.

3.2. Experiment 2: body temperature and sleep

Fig. 2 shows 1-h values of body temperature under
baseline conditions and after a 1-h social conflict. Under
baseline conditions, the average 24-h temperature was not
different between the wild type and b-endorphin deficient
mice. Also, there was no significant difference for the 12-h
light phase value but there was a trend for slightly lower
temperatures in the b-endorphin deficient mice during the
12-h dark phase (t51.81; P50.082).
During the conflict, body temperature increased and
gradually returned to baseline during the remainder of the
light phase. Although the baseline values did not differ
significantly between b-endorphin deficient and wild type

mice, we expressed the experimental values during and

after the conflict as deviations from the baseline. The
increase in temperature during the 1-h conflict was not
significantly different between b-endorphin deficient mice
and wild type animals. However, when the hour of the
conflict and the remaining 6 h of the light phase were
analyzed, there was a significant genotype3time interaction (F5,125 52.90; P50.016). In the b-endorphin deficient mice, the elevation of body temperature did not
persist as long as in the wild type mice (t-test, P,0.05 for
the last 2 h of the light phase). Thus, although the initial
rise in body temperature did not differ between the bendorphin deficient and wild type mice, the temperature
returned to baseline levels faster in the b-endorphin
deficient mice.
In this experiment, four b-endorphin deficient mice
showed clear signs of counter aggression as against eleven
animals that did not. However, the temperature response to
the conflict was similar in both groups. The increase in
temperature above baseline during the 1-h conflict, was not
significantly different between mice that showed counter
aggression and mice that did not and when the hour of the
conflict and the remaining 6 h of the light phase were
tested, there was no significant genotype3time interaction.
The amount of REM and NREM sleep, as well as the
accumulated NREM sleep SWE for 6-h intervals are
shown in Fig. 3. Under baseline conditions, there were no
major differences in the sleep patterns between b-endorphin deficient and wild type mice. Neither NREM nor
REM sleep patterns differed between the genotypes.
However, a slight difference in the temporal pattern of
accumulated SWE was found between wildtype and bendorphin deficient mice under baseline conditions (F3,81 5
3.150, P50.029). For separate 6-h block this only reached
statistical significance for the second half of the light phase

Fig. 2. Average hourly values of body temperature measured in wild type mice (left) and b-endorphin deficient mice (right) under baseline conditions (s)
and on the experimental day (d) when the animals were subjected to the stress of a 1-h social conflict during the 6th hour of the light phase. Dark bars
above the graph indicate the dark phase. Significant differences: B, relative to baseline (paired t-test, P,0.05); *, relative to wild type (two-sample t-test
for deviations from baseline, see text).

L.M. Vaanholt et al. / Brain Research 978 (2003) 169176

173

Fig. 3. Cumulative NREM sleep SWE, NREM sleep and REM sleep per 6-h interval in wild type mice (left) and b-endorphin deficient mice (right) under
baseline conditions (s) and on the experimental day (d) when the animals were subjected to a 1-h social conflict during the 6th hour of the light phase.
Data are expressed as averages (6S.E.M.). Significant differences: B, relative to baseline (paired t-test, P,0.05); *, relative to wild type (two-sample
t-test).

when the accumulated SWE was slightly higher in the wild

type mice (t52.12; P50.043).
After the conflict, there was an initial short lasting
decrease in NREM sleep the hour after the interaction but

this was compensated during the remainder of the light

phase (data not shown; totals for second half of the light
phase depicted in Fig. 3). In fact, NREM sleep was
increased above baseline levels during the first half of the

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L.M. Vaanholt et al. / Brain Research 978 (2003) 169176

dark phase in the b-endorphin deficient mice, but not the

wild type mice (Fig. 3). The changes in NREM sleep after
the conflict, expressed as deviations from baseline, were
not different between wild type mice and b-endorphin
deficient mice.
During the remainder of the light phase after the
conflict, the accumulation of NREM sleep delta power or
SWE was significantly increased above baseline levels in
both genotypes (Fig. 3). In the b-endorphin deficient mice,
SWE was still increased compared to baseline during the
first half of the dark phase but then slightly decreased
below baseline in the second half of the dark phase.
Overall, the changes in NREM sleep SWE after the
conflict relative to baseline were not different between
wild type mice and b-endorphin deficient mice.
Social defeat caused a strong initial suppression of REM
sleep during the remainder of light phase in both genotypes, which was followed by a significant increase during
the following dark phase (Fig. 3). Overall, the changes in
REM sleep after the conflict were not different between
wild type mice and b-endorphin deficient mice.
In the group of b-endorphin deficient mice, four mice
showed clear signs of counter aggression during the
conflict. To determine whether these mice had different
sleep patterns after the conflict as compared to mice that
did not show counter aggression, we analyzed both groups
separately. However, no differences in NREM sleep,
NREM sleep SWE, or REM sleep were found.

4. Discussion
After a social conflict, b-endorphin deficient mice had
higher corticosterone levels than wild type animals while
the peak temperature increase was not different between
the genotypes. In fact, body temperature returned to
baseline levels faster in the b-endorphin deficient mice.
During the interaction with an aggressive dominant conspecific, several of the b-endorphin deficient mice showed
clear signs of counter aggression whereas this was not seen
in any of the wild type mice. Overall, the b-endorphin
deficient mice and wild type mice had fairly similar sleep
patterns under baseline conditions and they showed similar
changes in the amount of NREM sleep, REM sleep and
accumulated SWE in response to a social conflict. In
addition, no differences were found in the sleep patterns of
mice that showed counter aggression and mice that did not.
Thus, these data do not support our hypothesis that bendorphin facilitates NREM sleep and suppresses REM
sleep after a social conflict. Although the complete lack of
endorphins from early development onwards might result
in mechanisms that compensate for this deficiency [10,29],
the present study demonstrates that the typical sleep
pattern after social defeat stress can still occur in the
absence of b-endorphin.
Our finding of an increased body weight in b-endorphin

deficient mice confirms an earlier report [29]. Cross

fostering studies suggested that the increase in body weight
resulted from a change in the maternal behavior of the
homozygote b-endorphin deficient mother, rather than a
change in the pup itself (Jackson Lab.). To prevent the
occurrence of a difference in weight due to maternal
effects, we used heterozygote parents for the breeding,
resulting in nests with mixed genotype. Nevertheless, a
difference in body weight of about 10% was found.
Therefore, the fact that b-endorphin deficient mice have an
increased body weight cannot simply be explained by a
change in the behavior of the homozygous mothers.
Alternatively, the lack of b-endorphin may affect growth
in the offspring via different pathways. An increase in food
intake by b-endorphin deficient mice might seem a plausible explanation for their elevated body weight. This,
however, is not supported by the literature since, in
general, opioid agents enhance feeding and opioid antagonists decrease feeding [17,24]. Perhaps, the lack of bendorphin during development causes a change in metabolism rather than food intake, which results in the increase
in body weight. The latter is weakly supported by the
finding of a trend towards a lower body temperature during
the active phase under baseline conditions in b-endorphin
deficient mice compared to wild types.
The display of counter aggression by the b-endorphin
deficient mice during the conflict was somewhat unexpected. With the protocol we used, experimental animals
rarely display such counter aggression when they are
facing the heavier and territorial cage owner. Perhaps the
counter aggression in the b-endorphin deficient mice was
due to their attenuated analgesia [29]. It is not excluded
that the b-endorphin deficient mice experienced more pain
when receiving bites from the dominant male and this may
have elicited defensive aggression and counter attacks.
Alternatively, it could be that the b-endorphin deficiency
affected aggressive behavior directly. It is known from the
literature that b-endorphin levels increase during a social
conflict, particularly in the submissive animals [8,13]. This
increase of b-endorphin in a defeated animal may function
to suppress aggression and stimulate submissive behavior
in these individuals, thereby preventing further attacks
from the dominant [11].
In addition to the occurrence of counter aggressive
behavior, the b-endorphin deficient mice also had small
but significant alterations in their physiological response to
the social interaction. At the end of the conflict, b-endorphin deficient mice had significantly higher corticosterone levels. This difference in corticosterone response
may be specific for social stress since Rubinstein et al. [29]
did not find a difference in the corticosterone levels after
restraint or ether stress. Such stimulus-specific modulation
of corticosterone release underscores the complex role of
endogenous opioids in stress (for review see [25]). Nonetheless, the results are in line with the finding that, of the
various opioids, b-endorphin in particular seems to have

L.M. Vaanholt et al. / Brain Research 978 (2003) 169176

an inhibitory effect on the hypothalamicpituitaryadrenal

axis [26].
The increased corticosterone response in b-endorphin
deficient mice compared to wild type animals did not
extend to other indicators of stress. The body temperature
increase during the conflict did not differ between wildtype
and b-endorphin deficient mice and, in fact, temperature
returned to baseline levels faster in the b-endorphin
deficient mice. The latter is in line with the finding that
intracerebroventricular injection of b-endorphins increases
body temperature [2,4] whereas administration of an
antagonist attenuates the temperature increase in response
to stress [23]. Importantly, the difference in both temperature and corticosterone response was not directly related to
the occurrence of counter aggression in the b-endorphin
deficient mice. Within this group, there were no differences
in these physiological responses between the animals that
did or did not show counter aggression.
In conclusion, the present study suggests that b-endorphin modulates the acute physiological and behavioral
response to social defeat, but the data do not support a
major role for b-endorphin in the regulation of sleep or
social stress-induced alterations in sleep.

[9]

[10]

[11]

[12]

[13]

[14]
[15]

[16]

[17]

[18]

Acknowledgements
[19]

The authors wish to thank Janna Arbuzova and Sarah

Smith for breeding and genotyping the mice; Julie Uherka
and Andy Rontal for technical support with the sleep
recordings and behavioral tests; and Martha H. Vitaterna
and Muriel Koehl for their help and valuable comments at
various stages of the project. This research was supported
by National Institutes of Health Grants AG-18200, AG11412, and HL-59598.

[20]

[21]

[22]

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