Behavioural Brain Research 167 (2006) 205–211
Role of ?-opioid and NMDA receptors in the development
and maintenance of repeated swim stress-induced
Heberto Suarez-Rocaa,∗, Jose Antonio Silvaa, Jose Luis Arcayaa,
Luis Quinteroa, William Maixnerb, Lorena Piˇ nerua-Shuhaibarc
aSection of Pharmacology, Instituto de Investigaciones Cl´ ınicas, Facultad de Medicina, University of Zulia,
Apartado Postal 1151, Maracaibo 4001-A, Venezuela
bDental Research Center, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455, USA
cDepartment of Neurobiology. INBIOMED, Fundacite-Zulia, Maracaibo 4001-A, Venezuela
Received 7 July 2005; received in revised form 6 September 2005; accepted 7 September 2005
Available online 6 October 2005
neurotransmitter systems modulate pain, we now evaluated the effect of pharmacological blockade of opioid and glutamate receptors subtypes on
forced swimming stress-induced hyperalgesia. Male rats were daily subjected to 10–20min of forced or sham swimming for 3 days and thermal
nociception was estimated twice, before each behavioral conditioning and 24h after the last, using hot plate test. Selective opioid and NMDA
receptor antagonists were administered i.p. either before each conditioning session or before the second nociception assessment. Unlike sham
swimming rats, forced swimming rats showed significant reductions in hot plate response latencies (hyperalgesia) after the last swimming session,
as compared to pre-stress values. Rats treated with the opioid receptor antagonists naloxone (0.1mg/kg, non-subtype-selective) and naloxonazine
(5mg/kg, ?1-subtype-selective), before each forced swimming, did not become hyperalgesic, whereas those treated before the second post-stress
assessment of nociception developed hyperalgesia. Naltrindole (0.5mg/kg, ?-subtype-selective) and nor-binaltorphimine (0.5mg/kg, ?-subtype-
selective) were inactive in both administration schedules. The efficacy of morphine (3–7.5mg/kg) to produce analgesia in forced swimming rats
stress assessment of nociception did not have hyperalgesia. Thus, swim stress-induced hyperalgesia might be initiated by the repeated stimulation
of ?-opioid and NMDA receptors but maintained only by the activity of NMDA receptors.
© 2005 Elsevier B.V. All rights reserved.
Keywords: Hyperalgesia; Stress; Forced swimming; Opioid receptor subtypes; Naloxone; Ketamine; Nor-binaltorphimine; Naltrindole
Stress can elicit either analgesia  or hyperalgesia [34,42]
produces a long-term increase in the behavioral responses to
noxious stimulation, which is associated with enhanced c-Fos
expression in neurons located in nociceptive areas of the spinal
cord . Changes in the central serotoninergic activity appear
∗Corresponding author. Tel.: +58 416 660 6505; fax: +58 261 759 7247.
E-mail address: firstname.lastname@example.org (H. Suarez-Roca).
to account, at least in part, for this swim stress-induced hyper-
algesia (SSIH) because very low doses of relatively selective
serotonin reuptake inhibitors clomipramine and fluoxetine, as
well as the serotonin precursor tryptophan , prevent SSIH.
On the other hand, the stress response is mediated , mod-
ulated , and terminated  by the release of endogenous
opioids, which are also inhibitory modulators of nociceptive
pathways [14,21,39]. Frequent release of endogenous opioids
as a consequence of repeated exposure to stressors could lead to
overactivation and desensitization of opioid receptors resulting
in a tolerance to the analgesic effects of endogenous opioids,
which might be implicated in the hyperalgesia observed after
repeated swim stress. Tolerance to the analgesic effects of opi-
0166-4328/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
H. Suarez-Roca et al. / Behavioural Brain Research 167 (2006) 205–211
oids is associated with hyperalgesia [24,25] and is related to
an increased activity of N-methyl-d-aspartate (NMDA) recep-
tors [12,40]. Thus, changes in the activity of opioid and NMDA
receptors could be implicated with the development and main-
tenance of SSIH. To test this hypothesis, we assessed the effect
of selective opioid and NMDA receptor antagonists on SSIH.
2. Materials and methods
Male Sprague–Dawley rats (Centro Biotecnol´ ogico IVIC, Caracas,
Venezuela) weighing 200–300g, were individually caged 3 days prior to the
behavioral procedure. Procedures were performed between 8:00 a.m. and 12:00
a.m., in the same room where the animals were housed. Animals were housed at
experimental protocol was approved by the Bioethical Committee for Scientific
Research on Animals at the University of Zulia.
2.2. Experimental protocol
On day 1, baseline thermal nociception measurement was obtained by using
the hot plate test described by Carter . Animals were gently placed on a hot
plate (IITC model 39D, USA) at 52.5◦C and the response latency, that is, the
time elapse either to jump or to lick their hind-limb, was registered. A cut-off
time of 45s was used to diminish the possibility of producing a burn in the rat.
Then, rats were subjected to a forced swimming by placing them in a plastic
for 10min. On days 2 and 3 rats were subjected to a similar swim stress for
20min. Control rats were subjected to a sham swimming session by allowing
them to wade in an identical cylinder but it contained only 2–4cm of water
at 24–26◦C. Both groups of rats were allowed to dry in a warm environment
(30–32◦C) immediately after each forced or sham swimming session for an
equivalent period of time. On day 4, i.e. 24h after the last swimming session,
thermal nociception was assessed again by using hot plate test. Additional hot
plate testing was carried out, on the same day, in rats subjected to post-stress
drug treatment (Fig. 1).
2.3. Pre-stress antagonist treatment
Several studies have demonstrated that opioid peptides [43,45] and gluta-
mate [8,37] are released during acute stress in several brain regions. Changes
in opioid receptor mediated neurotransmission can be modulated by NMDA
receptors [3,23]. Therefore, to determine if the repeated activation of opioid and
glutamate receptors during forced swimming stress is involved in the initiation
Fig. 1. Experimental protocol. Rats were subjected to a daily session of either
forced or sham swimming for three consecutive days. Drugs or vehicle (0.9%
NaCl) were administered i.p. either 30min before the stress session (pre-stress
treatment) or about 24h after the last stress session on day 4 (post-stress treat-
by measuring response latencies using a hot plate procedure.*For post-stress
drug treatment, thermal pain sensitivity was additionally assessed 30 or 60min
after the administration of the drug.
or ketamine, a NMDA receptor antagonist, prior to each forced or sham swim-
ming session. The non-subtype-selective opioid receptor antagonist naloxone
0.5mg/kg) , ?-opioid receptor selective antagonist naltrindole (0.5mg/kg)
, NMDA receptor antagonist ketamine (5mg\kg) were injected i.p. 30min
before each forced or sham swimming session. A single dose of the ?1-opioid
receptor antagonist naloxonazine (5mg/kg) was administered once, 1h before
the first swim stress, since only the irreversible action of the antagonist (after
(in the presence of the drug) includes ?2-sites . Control vehicle rats for each
group were injected with a similar volume of 0.9% NaCl.
2.4. Post-stress antagonist treatment
The spinal release of opioid peptides, such as dynorphin and the stimulation
the maintenance of SSIH, by examining the effects of selective opioid receptor
antagonists or the NMDA receptor antagonist ketamine on SSIH. The non-
subtype-selective opioid receptor antagonist, naloxone (0.1mg/kg), ?-opioid
receptor selective antagonist n-BNI (0.5mg/kg, NMDA receptor antagonist
the second hot plate assessment. Following a 30min period (30 and 60min for
ketamine), thermal nociception was re-evaluated. The assessment of the irre-
was conducted in the same manner with the exception that the hot plate assess-
ments were done 24h later. The doses of the antagonists used in this study have
been previously reported to block the opioid-mediated effects of stress on noci-
ception and/or escape behavior during the forced swimming test [19,38,44,47].
Control vehicle rats for each group were injected with a similar volume of 0.9%
2.5. Assessment of morphine analgesia
Since acute exposure to a variety of stressors releases endogenous opioids
[43,45], repeated exposure to stress might produce desensitization of opioid
receptor mediated mechanisms. In order to examine this possibility, we com-
pared the analgesic effect produced by morphine in groups of animals exposed
to repeated forced and sham swimming. Morphine (3 and 7mg/kg) i.p was
administered 24h after the last forced or sham swimming session. Analgesia
was estimated by measuring changes in the hot plate response latency, 30 and
60min after the injection of the drug. Baseline response latencies were obtained
24h after the last swimming procedure and prior to morphine injection.
2.6. Data analysis
The effect of morphine on nociception was analyzed by converting raw
hot plate response latencies to percentage of maximal possible analgesic
effect (%MPAE): %MPAE=100×(response latency after the drug−baseline
response latency)/(cut-off value−baseline response latency). Statistical evalu-
ation of the data was performed using either a one-way or a two-way analysis
of variance (ANOVA) followed by post hoc analysis with Bonferroni test. Sig-
nificance was assumed at p<0.05.
Fig. 2A shows the effects of opioid receptor antagonists
on SSIH. Rats treated with vehicle (saline) before each forced
swimming session had post-stress hot plate response latencies
about 34% shorter than those measured before the stress. In
contrast, rats subject to sham swimming did not display a sig-
response latencies in forced swimming rats were prevented by
the pre-stress administration of naloxone (0.1mg/kg i.p.) or the
H. Suarez-Roca et al. / Behavioural Brain Research 167 (2006) 205–211
Fig. 2. Effect of pre-stress treatment with selective opioid receptor antagonists,
in seconds (s). The abscissa shows the drug pre-treatment groups: 0.1mg/kg
naloxone (NALOX), naltrindole (NALT, 0.5mg/kg), nor-binaltorphimine (n-
BNI, 0.5mg/kg), naloxonazine (NLXZ, 5mg/kg) and 0.9% NaCl (saline) as
different from values obtained prior to conditioning with either forced or sham
swimming (two-way ANOVA with change from pre-exposure nociception as
repeated factor, followed by Bonferroni test; panel A: for change from pre-
exposure nociception F(1)=26.10, p=0.001; for antagonist treatment effect
F(4)=2.667, p<0.034; for interaction F(4)=2.116, p=0.081; panel B: for
change from pre-exposure nociception F(1)=0.004, p=0.942; for antagonist
treatment effect F(4)=1.103, p<0.358; for interaction F(4)=0.064, p=0.990).
?-selective opioid receptor antagonist naloxonazine (5mg/kg
i.p.) whereas ?-opioid receptor selective antagonist naltrindole
(0.5mg/kg i.p.) were ineffective (Fig. 2A). Fig. 2B shows that
pre-stress treatment with the opioid receptor antagonists did not
change hot plate response latencies in sham-conditioned rats,
suggesting that these drugs, at the dose used in this study, did
not have any significant effect per se on nociception.
When the opioid receptor antagonists, naloxone, naloxon-
azine, or nor-binaltorphine were administered on experimental
prior to third hot plate measurement), they were not able to
Fig. 3. Effect of post-stress treatment with selective opioid receptor antago-
nists on SSIH. The ordinate shows thermal pain response latencies measured
in seconds (s) before the first session and 24h after the last session of forced
swimming (panel A) or sham swimming (panel B). The abscissa shows the
post-treatment drug treatment group: 0.1mg/kg naloxone (NALOX), and nor-
binaltorphimine (n-BNI, 0.5mg/kg), naloxonazine (NLXZ, 5mg/kg), and 0.9%
NaCl (saline) as a control vehicle. Each value is the mean±S.E. from at least
10 rats.*Significantly different from the values obtained prior to conditioning
with either forced or sham swimming (two-way ANOVA with change from
pre-exposure nociception as repeated factor, followed by Bonferroni test; panel
A: for change from baseline nociception F(2)=24.63, p<0.001; for antagonist
treatment effect F(3)=0.550, p=0.649; for interaction F(6)=0.616, p=0.717;
panel B: for change from pre-exposure nociception F(2)=3.179, p=0.046; for
antagonist treatment effect F(4)=2.847, p=0.041; for interaction F(4)=0.520,
reverse the reduction in hot plate response latencies observed
in stress swim conditioned rats (Fig. 3A). In sham-conditioned
rats, n-BNI (0.5mg/kg) produced a significant reduction in the
response latencies of rats whereas naloxone and naloxonazine
were ineffective (Fig. 3B).
The administration of morphine (3 and 7.5mg/kg i.p.), 24h
groups (Fig. 4). Yet, the efficacy of morphine to produce anal-
H. Suarez-Roca et al. / Behavioural Brain Research 167 (2006) 205–211
Fig. 4. Effect of pre-exposure to forced swim stress on morphine analgesia.
swimming session. On the ordinate, morphine analgesia, expressed as %MPAE,
achieved 30min after the injection of morphine. Baseline response latency was
The abscissa shows the dose of morphine administered (i.p.). Each value is the
mean±S.E. from at least 12 rats.*Significantly different from its respective
sham swim control (two-way ANOVA followed by Bonferroni test: for swim
vs. sham swimming, F(1)=3.967, p=0.049; for morphine dose, F(1)=6.847,
p=0.011, for interaction, F(1)=0.357, p=0.552).
than in those subject to sham swimming, especially at a mor-
phine dose of 7.5mg/kg i.p. (Fig. 4).
Rats treated with the NMDA receptor antagonist ketamine
seen to rats treated with vehicle (saline) (Fig. 5). This dose of
ketamine did not have an effect on the hot plate response laten-
cies of sham-conditioned rats (Fig. 5).
Fig. 5. Effect of pre-treatment with NMDA receptor antagonist ketamine
on SSIH. The ordinate shows changes in hot plate response latencies
in seconds (s) from baseline measurements done before the first session
of forced or sham swimming. Baseline measurements (s): saline-forced
swimming=14.08±1.39; ketamine-forced swimming=11.21±1.25; saline-
abscissa shows treatment groups: ketamine (5mg/kg, i.p.) and 0.9% NaCl
(saline) as control vehicle. Each value is the mean±S.E. from at least 10 rats.
followed by Bonferroni test F(3,18)=6.970, p=0.003).
SSIH. The ordinate shows thermal pain sensitivity (hot plate response latencies)
measured in seconds (s). The abscissa shows the time periods of thermal pain
assessment. Ketamine (5mg/kg, i.p.) and saline (0.9% NaCl) were injected 24h
after the last forced (A) and sham swim (B) conditioning sessions. Each value
is the mean±SE obtained from at least seven rats.*Significantly different from
Bonferroni test. Panel A: for ketamine effect F(1)=19.75, p<0.0001, for pain
testing F(3)=3.565, p=0.0192; for interaction F(3)=3.092, p=0.034. Panel
B: for ketamine effect F(1)=0.966, p=0.329, for pain testing F(3)=0.881,
p=0.456; for interaction F(3)=0.189, p=0.903).
last stress and before the hot plate test, reversed to baseline pre-
stress values, the reduction in hot plate response latencies seen
evaluated the effect of 5mg/kg, i.p. ketamine on the hot plate
response latencies of control rats. In contrast to forced swim-
ming rats, sham-conditioned control rats treated with ketamine
showed response latencies that were not significantly differ-
ent from those displayed by vehicle (saline) treated controls
(Fig. 6B). This indicates that ketamine, at the very low dose
used in this study, did not affect per se nociception and did
not produce motor impairments at least concerning this pain
H. Suarez-Roca et al. / Behavioural Brain Research 167 (2006) 205–211
4.1. Opioid mechanisms in SSIH
In the present study, we corroborated our previous observa-
tions that repeated swim stress induces a thermal hyperalgesia
in rats . We found that pre-stress treatment with low doses
ment of SSIH. In addition, pre-stress treatment with ?1-opioid
receptor antagonist naloxonazine prevents SSIH, whereas n-
BNI and naltrindole were ineffective despite of the fact they
were used at doses that are both selective and effective to block
responses mediated by endogenous opioids. Indeed, 0.5mg/kg
n-BNI blocks the analgesia mediated by the release of endoge-
nous kappa receptor agonists during psychological stress 
while 1mg/kg naltrindole antagonizes the forced swimming
stress-induced antinociception assessed via the formalin test
. Thus, repeated activation of ?1-opioid receptors during
forced swim stress seems to be required for the induction of
Tolerance to morphine analgesia was observed in rats after
three consecutive exposures to the conditioning stressor (i.e.
forced swim stress). In agreement with our results, both tol-
erance to morphine analgesia and hyperalglesia are evoked by
chronic social defeat stress  and chronic restrain stress 
and tolerance to opioid analgesia can develop within 3 days
of daily administration of morphine . Since endogenous
opioids are released in the central nervous system in response
to noxious or aversive stressors , there might be an over-
stimulation of ?-opioid receptors during repeated stress that
would lead to desensitization of opioid nociceptive pathways,
tolerance to opioid analgesia, and consequently to hyperalge-
sia. Indeed, the blockade of ?-opioid receptors with naloxone
prevents the development of analgesic tolerance to the repeti-
tive administration of exogenous opioids  and pre-treatment
with naloxone or naloxonazine during exposure to swim stress
interfered with onset of hyperalgesia in the present study.
Repetitive swim stress may also induce the synthesis and
release of pro-pain evoking opioids. Recent experimental evi-
dence suggests that dynorphins seem to contribute to the ini-
tiation and maintenance of exaggerated pain states. Prepro-
dynorphin mRNA is increased in sensory areas of the spinal
cord in rodent models of inflammatory and neuropathic pain
[12,17,22,36], dynorphin A(1–17)enhances the release of sub-
stance P from primary afferents , and a single intrathecal
injection of dynorphin A induces a persistent allodynia .
expression in the spinal cord , it seems plausible that dynor-
phin overexpression may also occur in response to repeated
swim stress and thus contribute to SSIH by a receptor mech-
anism that remains to be elucidated.
4.2. Role of NMDA receptors in the SSIH
In the present study, the NMDA antagonist ketamine, at a
dose that did not alter rat performance in the hot plate test in
control rats (sham swimming), prevented and reversed SSIH,
suggesting the involvement of NMDA receptors in both the ini-
tiation and maintenance of this phenomenon. In line with our
results, several studies have found that both restrain and forced
swim stress induce glutamate and opioid release [5,8,37,43,45]
NMDA receptor level. Indeed, repeated stimulation of NMDA
receptors results in activation of intracellular pools of protein
kinase C that lead to uncoupling of ?-opioid receptors from
its associated G protein and the impairment of opioid trans-
mission . Interestingly, NMDA antagonists prevent both
hyperalgesia associated to morphine tolerance [20,25] and tol-
erance to morphine analgesia induced by repeated social defeat
stress  or by repeated administration of the opioid agonist
[3,23]. We have now found that SSIH was associated with
tolerance to morphine analgesia and was prevented by treat-
administered escalating doses of morphine, but not continuous
delivery by a pellet implantation, as well as repeated restraint
stress elevates key subunits of AMPA receptors (GluR1) and
NMDA receptors (NMDAR1) in the ventral tegmental area .
Since forced swimming stress activates both opioid and NMDA
systems [26,27], it could be plausible that repeated swimming
stress might produce an over-stimulation of the glutamate and
opioid neurotransmitter system that would end up interfer-
ing with inhibitory modulation of the opioid systems on pain
Finally, other excitatory neurotransmitters could be involved
in SSIH. For example, cholecystokinin peptides might also con-
tribute to the mechanisms by which NMDA/opioid receptors
influence SSIH since these peptides have anti-opioid activ-
ity and are increased in neuronal terminals following stress
in a manner that is sensitive to blockade with ketamine
4.3. Clinical implications
Repeated exposure to stress produces persistent functional
changes in nociception that might be related to alterations in
regulatory mechanisms mediated by endogenous opioids and
glutamate. Indeed, chronic stress early in life results in long-
term changes in opioid activity  so that persistent stress-
induced deficits in the endogenous opioid transmission would
alter nociception and other opioid-mediated functions to induce
hyperalgesia [6,34], immunosuppression  and hormonal
changes [29,30,45], feeding behavior alterations , anhedo-
nia and reduced locomotor activity . Thus, repeated expo-
sure to stress should be an important environmental factor that
contributes in humans to the initiation and maintenance of func-
tionally complex chronic pain syndromes by over-stimulation
and desensitization of opioid system as well as by an increased
activation of NMDA receptors.
This work was supported by grant from Condes-LUZ and
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