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Psych(clt1997.Vol. 21. pp. 997-1018
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EFFECT OF ISOLATION ON PAIN THRESHOLD
DIFFERENT EFF’ECTS OF MORPHINE
JEAN-PIERRE
COUDEREAU,
AND ON
CLAIRE MONIER, JEAN-MARIE
HENRIETTE
BOURRE and
FRANCES
INSERM U 26 - Hhpital Fernand Widal - Paris, France
(Final form, April 1997)
Abstract
Coudereau,
Jean-Pierre,
Effect of isolation
Claire Monier,
on pain threshold
Neuro-Psychopharmacol.
1.
Q Biol. Psychiat.1997.
The effect of three periods of isolation
on the pain treshold
2.
Jean-Marie
The pain threshold
2L.
effects
Frances:
of morphine.
pp. 997-1018.
Prog.
0 1997 Ekevier %ence
(8, 15 and 30 days ) were studied in mice
and the sensitivity
was unchanged
Bourre and Henriette
and on different
to morphine.
after 8 and 15 days of isolation
but increased
after 30 days of isolation.
3.
The analgesic
but increased
4.
The tolerance
isolation
effect of morphine was unchanged
after 8 and 15 days of isolation
after 30 days of isolation.
to morphine
but increased
analgesia
was unchanged
after 30 days of isolation
reduced).
997
after 8 and 15 days of
(morphine-induced
analgesia
was
IX
J.-P. Coudereau et al.
998
5. The physical
unchanged
on morphine
induced
after 8 and 15 days of isolation
It
6.
dependence
is
suggested
metabolism/absorption
that
but decreased
isolation
of morphine
by precipitated
may
in a different
withdrawal
was
after 30 days of isolation.
modify
the
way according
metabolism
the
as the treatment
is
unique or chronic.
: analgesia,
Keywords
dependence,
mice, morphine,
nociception,
social
isolation,
tolerance.
Introduction
Isolation
as
:
in rodents
increased
enhancement
(Valzelli,
aggression,
of the locomotor
decreased
activity,
learning,
alteration
modifications,
decreased
of the reactivity
conditioning,
to external
of
neurochemical
experiments
mechanisms
catecholaminergic
serotonergic
(Valzelli,
(Valzelli
Modifications
were
focused
underlying
on
isolation
the
; in
neurophysiological
particular,
the
role
of
1979, Yanai and Sze, 1983 ; Coudereau
et al,
systems (Simler et al, 1982 ; Oehler et al, 1985).
of the opioid system are also induced by isolation.
It was observed
mice (Bonnet et al., 1976) and in rats (Schenk et al., 1982) a significant
receptors
and
1978 ; Frances et al, 1980 ; Oehler et al, 1985, 1987)
and Bernasconi,
1995) and GABAergic
increased
stimuli
et al, 1996).
number
opioid
such
et al, 1975 ; Einon et al, 1978 ; Schenk et al, 1983, 1985 ;
1974, Morgan
Coudereau
A
can induce a great number of behavioural
in the brain as a result of isolation.
in mice following
48 or 72 hours of isolation
1990). A single day of isolation
increased
rats (Panksepp, .1980) and a short-term
nest caused a significant
The hot-plate
analgesic
tail-shock
(Konecka
latencies
of
were
and Sroezynska,
induced vocalizations
(5 min) isolation
response
in
reduction
from mother,
to heat (48°C) relative
in young
siblings and
to non isolated
siblings (Kehoe and Blass, 1986a).
The pharmacological
altered by isolation
effect
of drugs,
particularly
which is coherent with an alteration
Katz and Steinberg
(1972)
De Feudis et al. (1976)
and Blass (1986b)
showed
that, in isolated
was greater
than in non isolated
that of opiates,
Kostowski
rats, the analgesic
rats, whereas
may also
be
of the opioid system. Indeed,
et al. (1977)
Kehoe
effect of morphine
Adler et al. (1975a),
Puglisi-Allegra
Effect of isolation on different effects of morphine
and 01ivierio(1983)
isolated
rats regarding
results, Pankseep
was
showed
animals.
the analgesic
(1980) observed
less effective
housed
that no difference
in reducing
These
effect
Another
point seems important
naloxone
to morphine
may be altered
relative
induced
following
naloxone
factors
isolation
administration
administration
: (2) tolerance
in socially
due to the
symptoms
induced
by
and Marks-
rats show less severe withdrawal
than grouped rats.
in mice, the effect of isolation
: (1) analgesia
to morphine
than
perhaps
: the effect of chronic treatments.
were
The duration
compared.
the effect of every duration of isolation
treatment
to these
3-4 days, morphine
since Adler et al. (1975b)
that isolated
: 8, 15 and 30 days of isolation
an acute
In opposition
analgesia.
and on different effects of morphine.
authors compared
and non
vocalizations
and the withdrawal
The aim of this work was to study,
threshold
isolated
conlusions
to opiates
analgesia
Kaufman and Lewis (1984) reperted
symptoms following
of morphine.
led to different
different methods used to assess morphine
The tolerance
between
that, in young rats isolated
tail-shock
results
occurs
999
and
analgesia
on the pain
of isolation
was a main
In the same study, the
on an effect observed
on effects
observed
and dependence
after
after
chronic
to morphine.
Methods
Animals
Male Swiss NMRI mice (20-24 g at the beginning
from CERJ,
Genest
rooms
thermostatically
were
St Isle 53940
(France).
maintained
of the experiment)
The maintenance
at 21 + 1°C with
were obtained
and experimental
12 hours
light/dark
schedule (light on from 8 a.m. to 8 p.m.). Food and water were freely available.
1000
J.-P.
Coudereau et aL
Druas
Morphine sulfate (Francopia, France) and naloxone hydrochloride (5 mg/kg) (Endo
Laboratories, New-York, USA) were dissolved in demineralized water. The volume of
injection was 0.2 ml120g body weight. Administration
intraperitoneal
were performed by the
route (i.p.). The doses of morphine were expressed in base. The
differents doses used are reported in the experimental procedure for each test.
Experimental Procedure
Housina Conditions : Mice were housed in groups of 6 in home cages of 30x20~10
cm or isolated in home cages of 24x10~8 cm. The mice were 4-5 weeks old at the
beginning of the isolation. There were three periods of social isolation : 8, 15 and 30
days. The animals were isolated from others with respect only to tactile stimuli.
Different groups of mice were used for every duration of isolation and, also, for
every social group. As an example, the mice used for 30 days isolation and their
grouped controls were introduced in the animal house at the same date ; then, half
of the mice were isolated and the other half was maintained in collective cages in the
same animal house, for the 30 days before the performance of the test. The
experiments relative to one test and one duration of isolation were performed during
the same days for the isolated mice and also for the corresponding non isolated
mice.
Assessment of Pain Threshold and Analaesic Effect of Morphine. Pain threshold
and painful
responses were determined
using a 55 21°C
hot-plate
as the
nociceptive stimulus and the latency to paw-lick or an attempt to escape by jumping
as the painful response. Pain threshold was tested just before the injection of
morphine (control latency). Analgesia was tested 20, 40, 60, 100, 150, 200 and 250
minutes after the injection of morphine (8mg/kg) (test latency), between 10.00 a.m.
and 4.00 p. m.
The percentage of analgesic effect at each time was calculated
according to the following formula : % analgesic effect = 100 x (test latency - control
latency) I (cut-off time - control latency). To prevent tissue damage, the mice that
showed no response within 60 seconds (cut-off time) were removed from the hotplate.
Effect of isolation on different effects of morphine
Assessment of the Tolerance to Morphine Analaesia.
1001
The analgesic effect of
morphine was assessed using the same procedure described previously.
The
assessment of the analgesic effect of morphine was studied by the same procedure
than previously. Mice were treated with morphine (10 mg/kg) daily for 5 days. For
isolated-mice and their corresponding grouped
mice, morphine was administerted
during the latter part of isolation.
The analgesic effect was measured 30 minutes after the injection of morphine. The
test trials were performed between 10.00 a. m and 1.OOpm. The first day, the pain
threshold was measured before morphine injection (to day 1).
The analgesic effect obtained every day was compared to the analgesic effect of the
first day. The percentage of analgesic
effect was calculated
according to the
following formula : % analgesic effect = 100 x (latency at day d - latency at to day 1 I
(cut off time - latency at to (day 1).
A diminution of the percentage of analgesic effect indicated a development of
tolerance to morphine analgesia.
Assessment of the Phvsical Dependence to Morphine. Mice received 50 mglkg at
10 a. m. and 4 p. m. on day 1, 50 mglkg at 10 a. m. and 2 p. m. and 100 mglkg at 6
p. m. on day 2, 50 mg/kg at 10 a. m. on day 3. The withdrawal syndrome was
precipitated at 4 p. m. on day 3 with an injection of naloxone (5 mglkg). For isolatedmice and their corresponding controls morphine was administered during the latter
pan of isolation.
Each mouse was placed in a glass cylinder (30 cm high, 15 cm diameter) and
observed during 15 minutes after naloxone injection.
The severity of the withdrawal syndrome was quantified by the number of repetitive
vertical jumps.
All mice were used only once. Mice were killed using CO2 in a special container
Data Analvsis
Results were expressed as mean f standard error to the mean (S.E.M.). The pain
threshold, the dependence and the area under the curve were analyzed using the
Student’s t-test. For the morphine
analgesia
and the tolerance
to morphine
J.-P. Coudereau et al.
1002
analgesia, the results were analyzed using a one-way analysis of variance for
repeated measures followed by the Bonfferroni’s tests for each duration of isolation.
There were 1O-l 5 animals in each group.
Results
Threshold of Nociceotion
Figure 1 indicates that isolated mice (8 days (t=0.28) or 15 days(t=1.41) of
isolation) did not present a pain threshold different from that of non isolated mice.
On the other hand, after 30 days of isolation, the pain threshold was higher than in
grouped animals (t=4.20).
Morphine Induced Analaesia
Morphine induced an analgesia in isolated and in non isolated mice. There was no
significant difference with 8 and 15 days of isolation (Fig 2A and 28). In animals
isolated during 30 days, the analgesic effect of morphine was significantly
higher
(Bonferronni test) at 20 and 40 minutes (Fig 2C). The analgesic effect of morphine
increased considerably for 30 days isolated animals at 20, 40 and 60 minutes
(increase from 10 to 30 % of analgesic effect).
Analgesia was still present in isolated and non isolated animals at 250 minutes (5 to
12 % of analgesic effect).
Develooment of the Tolerance to Morphine Analaesia
Whatever the conditions
of rearing (isolation
or non isolation),
there was a
tolerance to morphine analgesia deveeloped over the 5 days, as reflected
by the
progressive decrease in percentage of analgesia following repeated administration
of the same dose of morphine (Fig 3). An isolation of 8 or 15 days didn’t modify the
analgesic tolerance to morphine (Fig 4A and 48). However, following 30 days of
Effect of isolation on different effects of morphine
isolation,
isolated
the tolerance
to morphine
analgesia
was extremely
1003
increased.
mice, the area under the curve was half that observed
Indeed,
in non isolated
in
mice
(Fig 4C).
Development
In mice
of the Phvsical
chronically
induced jumping
Dependence
receiving
neither
water,
to Morphine
the
in mice isolated
(n=5) nor in their corresponding
administration
of naloxone,
5 mg/kg,
8 days (n=5), 15 days (n=5) or 30 days
non isolated controls of 8 days (n=5), 15 days (n=5)
or 30 days (n=5).
Naloxone
(5 mg/kg)
receiving
morphine.
observed
in isolated
showed a tendency
days of isolation,
Threshold
The
a withdrawal
withdrawal
and non isolated
to decrease
the withdrawal
syndrome
animals.
the withdrawal
syndrome
syndrome
precipitated
in mice
by
A period of isolation
syndrome
was significantly
chronically
naloxone
was
of 8 or 15 days
(Fig 5A and 5B). After 30
less important
(Fig 5C).
of Nociception
The threshold
non isolated
of nociception
was higher
in 30 days isolated
mice (+62%) than in
mice. Different types of acute stressors (like an immobilization)
an increase
opioids
precipitated
of threshold
of nociception
resulting
from an increased
produce
release
of
(Amir et al, 1980 ; Bodnar et al, 1980). Unlike acute stress, which reduces
pain responsiveness,
prolonged
exposure
to stress leads to enhanced
reactivity
pain (Amir et al, 1980 ; Bodnar et al, 1980). The role of social isolation
prolonged
stress has been debated
The present
findings
(1983) who reported
isolated mice.
(Anisman,
are in accordance
that isolated
to
in terms of
1978).
with those of Puglisi-Allegra
mice showed
higher
and Oliverio
pain thresholds
than non
1004
J.-P. Coudereau et al.
0
non isolated
m7 isolated
0-
A
6-
-r-
0
8
1
B
6
C
***
Fig 1 : Effect of isolation on pain threshold measured on the hot-plate test
The durations of isolation were: A : 8 days (ns), B : 15 days (ns), C : 30 days
- p<O.OOl (Student’s t test)
Effect of isolation on different effects of morphine
O2’0
t
isolated
+
non isolated
loo0
Time (min .I
35
B
30
01
20
40
60
1000
Time (min.)
l
**
f
3530252015IOS-
Time (min.)
Fig 2 : Effect of isolation on analgesia induced by morphine (8 mg/kg)
The durations of isolation were : A : 8 days ; ANOVA : F(13-182) = 2.015 p<O.O5, B :
15 days ; ANOVA : F(13-182) = 3.03 p<O.OOl, C : 30 days ; ANOVA :F( 13-198) =
4.109 p<O.OOl qcO.05 *p<O.Ol (Bonferronni test)
1005
J.-P.
Coudereau
1006
40
et al.
1
--c isolated
-+ non isolated
1
2
3
4
5
Days
407
35-
i3
Days
s
b
3025-
._
0
8
:
*
0
3
20-
*
io155-d
Days
Fig 3 : Effect of isolation on the tolerance to morphine analgesia: temporal
development. The durations of isolation were : A : 8 days ; ANOVA : F(9-140) = 9.10
pcO.001, B : 15 days ; ANOVA : F(9-135)
6.86 pcO.001, C : 30 days ; ANOVA :
q
F(9-130) = 8.6 p<O.OOl.
lp<O.O5 (Bonferronni
test)
% analgesic effect
area under the curve
(Dl-D5)
% analgesic effect
area under the curve
(Dl-D5)
% analgesic effect
area under the curve
(Dl-D5)
J.-P. Coudereau et al.
50
8
40
E
.z
%
30
i
*O
z
10
50-
0 non isolated
&J isolated
B
I! 4o
.=
%
30-
“E
5
20-
2
lo-
Fig 5 : Effect of isolation on naloxone-precipitated withdrawal in morphine-dependent
mice q~O.05 (Student’s t test). The durations of isolations were: A: 8 days, B: 15
days, C: 30 days
Effect of isolation on Merent effects of morphine
1009
The increase of nociception threshold in 30 days isolated mice can be explained by
an increased release of endogenous opioids or by an increase of sensitivity to
endogenous opioids.
Analaesia Induced bv Morohine
Morphine induced an analgesia in both isolated and non isolated mice. Action
mechanisms of the morphine’s analgesic effect involved a complex interaction of
peripheral and central nervous systems. Spatial transections markedly reduce the
antinociceptive
activity of morphine (Ling and Pastemak, 1983). Anatomical and
physiological studies have confirmed the presence of descending pathways from the
brainstem to the dorsal horn of the spinal cord that are strongly influenced by
morphine (Besson and Chaouch, 1987). Within the brainstem, detailed studies
established
the
importance
of a number
of specific
regions,
including
the
periaqueductal gray, nucleus raphe magnus and locus ceruleus (Jacquet and Lajtha,
1973 ; Bodnar et al, 1988).
The analgesic effect of morphine in 30 days isolated animals was greater than in
non isolated animals, at 20 and 40 minutes after injection of morphine (passage from
10 to 30% of the analgesic effect). These differences in results were observed only
with a period of isolation of 30 days (and not with 8 and 15 days of isolation).
The serotonin seems to be involved in the analgesic effect of morphine. Samanin et
al (1970) have observed a diminution of 5hydroxytryptamine
in midbrain raphe
lesioned rats. This decrease in the level of serotonin was associated a with reduced
analgesic effect of morphine. Garattini et al (1967) have shown a decrease of
serotonin’s turn-over in isolated mice. Our findings cannot explain these results
since the analgesic effect is greater in our isolated animals.
The present results agree with those of Katz and Steinberg (1972) Defeudis et al
(1976) Kostowski et al (1977). These authors showed that in isolated animals (rats
or mice) the analgesic effect of morphine was greater than in non isolated animals.
Our results do not agree with those of Adler et al (1975a), Puglisi-Allegra
Oliver0 (1983) who showed that
and
no difference exists between isolated and non
isolated rats regarding the analgesic response to morphine.
J.-P. Coudereau et cd.
1010
Development
of the Tolerance
Chronic administrations
effect of morphine.
alterations
of morphine
The tolerance
in second
suggests
to Morphine
cholecystokinin
(CKK)
lead to a decreased
(Blanchard
systems
antagonists,
tolerant
animals.
and Fields,
However,
as proglumide
1983) restore
days
of
isolation
increased
Some
evidence
For example,
(Dourish
et al,
morphine’s
analgesic
;
1988
and amitriptyline
(Pick
potency
in
actions are also seen in naive animals,
implying that they are not directed specifically
Thirty
1988).
number and
down-regulation).
such as nefazodone
these facilitatory
to the analgesic
in receptors
and Chang,
(and/or
such
Watkins et al, 1984) and antidepressants
et al, 1992 ; Botney
response
may be due to changes
messenger
a role of antagonistic
Analgesia
against the mechanisms
the
tolerance
to morphine
to
of tolerance.
morphine
analgesia
analgesia
(+200%).These
increases
in the tolerance
may be explained
by a different
metabolism
(or elimination)
of morphine
between
isolated
as the prototype
of u agonist.
However,
morphine
and non
isolated animals.
Morphine
is well-known
affinity not only for u but also for 6 and k receptors
(1992) have shown that inactivation
antagonist,
morphine
nor-binaltor-phinine
analgesia
Considering
decrease
increased
system by a highly selective
the development
of tolerance
k
to
in mice.
these resuits, it may be suggested
in the sensitivity
in the tolerance
(Wood et al, 1981). Suzuki et al
of the k opioid
(nor-BNI)
has an
that social isolation
can induced a
of kappa opioid system which would result in an increase
to morphine
analgesia.
Dependence
The degree
withdrawal
syndrome
number
of physical
sydrome
dependence
(Way
can be estimated
of methods
Weinstock,
syndrome
1969).
The
by the quantification
quantification
of the
by a multitude of signs and symptoms.
to estimate
1971; Adler
precipitated
can be assessed
et al,
this syndrome
et al, 1975b).
by a receptor
(Way
opiod
antagonist
There are a great
et al, 1968,
The most pertinent
of the
withdrawal
Marshall
and
sign of the withdrawal
was
repetitive
jumping
(Frances et al, 1992; Ohta and Kaneto, 1992).
The naloxone
non isolated
precipitated
animals.
withdrawal
An isolation
syndrome
was observed
in both isolated
of 8 and 15 days is not sufficient
and
to induce
a
Effect of isolation on different effects of morphine
significant
difference
and non isolated
syndrome
in the severity
animals.
probably
induce
syndrome
After 30 days of isolation
was decreased
that a long period
of the withdrawal
compared
of isolation
to non isolated
(30 days)
some changes
1011
between
the severity
animals,
These results showed
can alter the withdrawal
in the mechanisms
isolated
of the withdrawal
implicated
syndrome
and
in the dependence
and/or abstinence.
Our results
(1984)
agree
who
naloxone
with those of Adler et al (1975b),
showed
that
precipitated
in rats isolated
withdrawal
Katz and Steinberg
during
syndrome
(1972) reported
a long
after
a production
that the long term isolation
dependence.
(1972) study, the other signs of the withdrawal
It has been reported
prolonged
et al, 1972).
isolation
1978; Anisman
isolation
release,
particulary
(Valzelli
and Sklar,
(30 days)
can
and Garattini,
tolerance
had received
less morphine
(the tolerance
development
is greater)
of physical
on the same mechanisms
and Kaneto,
1992)
the tolerance
indicates
accelerate
explanation
amines
and dependence,
mechanism
the catabolism
that in these
changes,
some
1973; Weinstock
metabolic
syndrome
and Duggan,
changes
was smaller.
to morphine
1984 ; Kaneto
on morphine
but deserves
of
(synthesis,
can produce
response
that the modifications
for isolation
et al,
a
in isolated animals.
on and tolerance
of chronic morphine
is only speculative
in the turn
1985). A long period
and these modifications
syndrome
two species,
particularly
all things look as if mice isolated
it may be suggested
to and the dependence
a common
reported
1972; Modigh,
; their withdrawal
(Johnson
Steinberg’s
amines in the brain can
than social mice : their analgesic
dependence
rats did
abrupt withdrawal
have not been noted.
and Thurmond,
in animals
in the severity of the withdrawal
Regarding
the
jumping in both mice and rats (Way et al,
1981; Lasley
induce
of immature
in Katz and
syndrome
It has also been
turn over) of the biogenic
decrease
However,
can induce some biochemical
over of brain amines
(12 weeks)
rats following
that drugs that interfere with biogenic
affect some signs of withdrawal,
1968; Collier
period
and Lewis
showed a smaller number of jumps.
not result in any greater weight loss than in grouped
of morphine
Marks-Kaufman
following
; it is suggested
Although
the
did not depend
et al., 1985; Ohta
in the same way of
30 days of isolation
that isolation
(or reduce its absorption).
to be verified.
30 days
was smaller
may
This likely
1012
J.-P. Coudercau et d
Conclusion
The present results show that a long period of isolation (30 days) is necessary to
observe modifications of the pain threshold and of the sensitivity to morphine. After
an acute treatment an effect of morphine (analgesia)
contrary, tier
was increased. On the
chronic treatments things appear as if the dose of morphine was
lessened : the tolerance is increased and the dependence is decreased. These
results suggest that isolation may modify the metabolism/absorption of morphine in a
different way according as the treament is unique or chronic.
Acknowledaements
This work was supported by the “lnstitut National de la Sante et de la Recherche
Medicale”.
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