Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms
We assessed the effect of sleep deprivation on the pain thresholds in the thermal and chemical nociceptive tests. Adult male Wistar rats and mice were randomly assigned to the three groups, with no sleep deprivation (control), subjected to 24-h-long sleep deprivation, and sleep-deprived and treate...
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irk-123456789-1483702019-02-19T01:29:46Z Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms Ibironke G. F. Ajonijebu C. O. Ibironke We assessed the effect of sleep deprivation on the pain thresholds in the thermal and chemical nociceptive tests. Adult male Wistar rats and mice were randomly assigned to the three groups, with no sleep deprivation (control), subjected to 24-h-long sleep deprivation, and sleep-deprived and treated with either an H2 (histamine) receptor antagonist, cimetidine, or a cholinergic receptor blocker, atropine, before deprivation.Sleep deprivation led to significant decreases in both hot plate and tail withdrawal latencies in the thermal tests, a significant increase in the number of writhings in the acetic acid-induced writhing test, and significant prolongation of the licking time in the formalin test (P < 0.05 in all cases). All changes in the thermal and chemical tests denote noticeable hyperalgesia. Prior administration of both cimetidine and atropine significantly reversed these hyperalgesic changes caused by sleep deprivation as revealed by increases in the thermal latencies in both tests used. We, therefore, conclude that both histaminergic and cholinergic systems play significant roles in sleep deprivation-induced hyperalgesia Ми оцінювали впливи позбавлення сну на пороги болю, що визначалися в термальних та хімічних ноцицептивних тестах. Дорослі самці щурів лінії Вістар та мишей були рандомізовано розподілені на три групи: тварини без депривації (контроль), піддані позбавленню сну протягом 24 год, а також піддані позбавленню сну з попереднім уведенням або антагоніста гістамінових H2-рецепторів ціметидіну, або блокатора холінергічних рецепторів атропіну. Позбавлення сну призводило до вірогідних зменшень латентних періодів моторних реакцій у тестах гарячої пластинки та відсмикування хвоста, істотного збільшення кількості «корчів» у відповідному тесті з внутрішньоочеревинним уведенням оцтової кислоти та до вірогідного збільшення тривалості лизання кінцівки у формаліновому тесті (P < 0.05 у всіх випадках). Зміни індексів у всіх термальних та хімічних тестах свідчили про розвиток помітної гіпералгезії. Попередні введення ціметидину та атропіну значною мірою усували ці прояви гіпералгезії, викликані позбавленням сну, на що вказувало збільшення латентних періодів захисних реакцій в обох використаних термальних тестах. Отже, і гістамінергічна, і холінергічна системи відіграють істотну роль у гіпералгезії, викликаній позбавленням сну 2014 Article Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms / G. F. Ajonijebu C. O. Ibironke // Нейрофизиология. — 2014. — Т. 46, № 5. — С. 463-467. — Бібліогр.: 18 назв. — англ. 0028-2561 http://dspace.nbuv.gov.ua/handle/123456789/148370 616.8 – 009.621 en Нейрофизиология Інститут фізіології ім. О.О. Богомольця НАН України |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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DSpace DC |
| language |
English |
| description |
We assessed the effect of sleep deprivation on the pain thresholds in the thermal and chemical nociceptive tests. Adult male Wistar rats and mice were randomly assigned to the three
groups, with no sleep deprivation (control), subjected to 24-h-long sleep deprivation, and
sleep-deprived and treated with either an H2 (histamine) receptor antagonist, cimetidine, or a
cholinergic receptor blocker, atropine, before deprivation.Sleep deprivation led to significant
decreases in both hot plate and tail withdrawal latencies in the thermal tests, a significant
increase in the number of writhings in the acetic acid-induced writhing test, and significant
prolongation of the licking time in the formalin test (P < 0.05 in all cases). All changes in
the thermal and chemical tests denote noticeable hyperalgesia. Prior administration of both
cimetidine and atropine significantly reversed these hyperalgesic changes caused by sleep
deprivation as revealed by increases in the thermal latencies in both tests used. We, therefore, conclude that both histaminergic and cholinergic systems play significant roles in sleep
deprivation-induced hyperalgesia |
| format |
Article |
| author |
Ibironke G. F. Ajonijebu C. O. Ibironke |
| spellingShingle |
Ibironke G. F. Ajonijebu C. O. Ibironke Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms Нейрофизиология |
| author_facet |
Ibironke G. F. Ajonijebu C. O. Ibironke |
| author_sort |
Ibironke |
| title |
Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms |
| title_short |
Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms |
| title_full |
Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms |
| title_fullStr |
Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms |
| title_full_unstemmed |
Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms |
| title_sort |
sleep deprivation-induced hyperalgesia in rodents: some neurochemical mechanisms |
| publisher |
Інститут фізіології ім. О.О. Богомольця НАН України |
| publishDate |
2014 |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/148370 |
| citation_txt |
Sleep Deprivation-Induced Hyperalgesia in Rodents: Some Neurochemical Mechanisms / G. F. Ajonijebu C. O. Ibironke // Нейрофизиология. — 2014. — Т. 46, № 5. — С. 463-467. — Бібліогр.: 18 назв. — англ. |
| series |
Нейрофизиология |
| work_keys_str_mv |
AT ibironke sleepdeprivationinducedhyperalgesiainrodentssomeneurochemicalmechanisms AT gfajonijebucoibironke sleepdeprivationinducedhyperalgesiainrodentssomeneurochemicalmechanisms |
| first_indexed |
2025-07-12T19:14:32Z |
| last_indexed |
2025-07-12T19:14:32Z |
| _version_ |
1837469717879586816 |
| fulltext |
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2014.—T. 46, № 5 463
UDC 616.8 – 009.621
G. F. IBIRONKE1 and C. O. AJONIJEBU1
SLEEP DEPRIVATION-INDUCED HYPERALGESIA IN RODENTS: SOME
NEUROCHEMICAL MECHANISMS
Received 24.08.13
We assessed the effect of sleep deprivation on the pain thresholds in the thermal and chemi-
cal nociceptive tests. Adult male Wistar rats and mice were randomly assigned to the three
groups, with no sleep deprivation (control), subjected to 24-h-long sleep deprivation, and
sleep-deprived and treated with either an H2 (histamine) receptor antagonist, cimetidine, or a
cholinergic receptor blocker, atropine, before deprivation.Sleep deprivation led to significant
decreases in both hot plate and tail withdrawal latencies in the thermal tests, a significant
increase in the number of writhings in the acetic acid-induced writhing test, and significant
prolongation of the licking time in the formalin test (P < 0.05 in all cases). All changes in
the thermal and chemical tests denote noticeable hyperalgesia. Prior administration of both
cimetidine and atropine significantly reversed these hyperalgesic changes caused by sleep
deprivation as revealed by increases in the thermal latencies in both tests used. We, there-
fore, conclude that both histaminergic and cholinergic systems play significant roles in sleep
deprivation-induced hyperalgesia.
Keywords: sleep deprivation, thermal tests, writhing test, formalin test, pain thresholds,
histamineergic and cholinergic systems.
1 Department of Physiology, College of Medicine, University of Ibadan,
Ibadan, Nigeria.
Correspondence should be addressed to G. F. Ibironke
(e-mail: gibironk@yahoo.com).
INTRODUCTION
The interaction between such phenomena as sleep and
pain has been studied for many years. Although it is well
documented that subjects with different pain syndromes
suffer from sleep disturbances [1, 2], the direction of
effects in this relationship is still a matter of debate; the
effects observed may not be unidirectional. A few studies
in humans support the notion that sleep deprivation
produces hyperalgesia [3]. The pioneering study of
the effect of sleep deprivation on pain perception was
performed by Cooperman et al. [4]. Although the finding
of the hyperalgesic effect of sleep deprivation was
recently replicated by Onen et al. [5], some other authors
failed to demonstrate any effect of total sleep deprivation
on nociception and pain [6, 7]. Most of studies on
the relationship between sleep deprivation and pain
perception were descriptive and were not focused on the
mechanisms of action. First hints on the mechanism of
action responsible for the hyperalgesic effect of sleep
deprivation were provided by Ukponmwan et al. [8]. The
significance of opioidergic and serotonergic processes
in mediating mechanisms of the hyperalgesic changes
produced by sleep deprivation were discussed [9].
We tried to further investigate the relationship
between sleep deprivation and pain perception in view
of the controversial reports, as well as to identify
some neurochemical mechanisms underlying the
hyperalgesic effect.
METHODS
Animals. Male albino rats (180-220 g) and mice
(50-80 g) were used in the study. They were housed
and bred under standard vivarium conditions (room
temperature and a 12/12 h light/dark cycle). The
animals were fed with standardized mouse cubes and
provided with water ad libitum.
Sleep Deprivation. A sleep deprivation technique
adapted for rodents was used. This is based on the fact
that a decrease in the muscle tone during sleep results
in a touch to water and waking. This method results in
a complete abolition of paradoxical sleep and a 37%
decrease in slow-wave sleep [10]. In all respective
tests, cimetidine and atropine were administered 60
min before sleep deprivation.
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2014.—T. 46, № 5464
G. F. IBIRONKE and C. O. AJONIJEBU
Hot Plate Test. A mild modification of the standard
hot plate technique was used [11, 12]. Rats of the
control and sleep-deprived groups were placed on a
hot (55 ± 2°C) plate set, and the time taken to start
licking the paws or jump off from the plate was
measured as the hot plate latency. A 60 sec cut-off time
was imposed to avoid excessive tissue damage.
Tail Withdrawal Test [13]. Each animal was gently
held with a hand towel, and the terminal 3 cm of the
tail was immersed in a water bath (50° ± 1°C). The
time taken by animals to flick their tails out of water
(tail-flick latency) was measured.
Formalin Paw Licking Test [14]. Experimental rats
were injected with 20 µl of 1% formalin into the dorsal
surface of the left hind paw. The duration of licking
the injected paws (licking time) observed within the
first 5 min post-injection (early phase) and for 10 min
starting at the 20th min post-injection (late phase)
were measured.
Acetic Acid-Induced Writhing Test [15, 16].
Experimental mice were i.p. injected with 0.2 ml of
3% acetic acid to induce the characteristic writhing.
The number of writhings (evoked by visceral pain)
observed within a 5 to 10 min post-injection interval
was calculated.
RESULTS
Nociception Tests. Control rats (n = 6) took about 5
sec (5.17 ± 0.17 sec, on average) to initiate licking the
paws or to attempt to jump off from the hot plate in the
respective thermal nociception test. At the same time,
sleep-deprived rats (n = 6) manifested such motor
reactions with appreciably shorter latencies (mean,
1.84 ± 0.41 sec; P < 0.05) (Fig. 1A).
In another thermal test (tail flick), control rats in
most cases withdrew their tail from hot water with a
4–5.5 sec delay (4.68 ± 0.51 sec, on average). The rats
of the experimental group realized this motor response
in 3.00 ± 0.39 sec, on average (i.e., the respective
latency was only 64% of that in the control; P < 0.05)
(B).
In the formalin test, the total time of paw licking in
the control group (n = 6) within the first 5-min-long
post-injection interval was 56 ± 1.1 sec, while in sleep-
deprived rats (n = 6) the respective value was 88 ±
± 11.3 sec, i.e. 57% greater. Thus, sleep deprivation
leads to intensification of acute pain in the mentioned
test (Fig. 2B, 1). Within the subsequent time interval,
from the 20th until the 31st min post-injection,
episodes of licking the impaired limb lasted 38.8 ±
± 2.1 sec, on average. In sleep-deprived animals, the
analogous episodes were more than two times longer
(80.5 ± 9.0 sec, on average; P < 0.05) (Fig. 2B, 2).
In other words, sleep deprivation enhanced “late”
(inflammatory) pain in the formalin test similarly to
“early” acute pain, and the increment was noticeably
greater than that in the latter case (B).
A parallel, to a significant extent, situation was
observed in the acetic acid-induced writhing test
on mice. Under conditions of our experiments (see
Methods), i.p. injections of acetic acid into control
mice (n = 60) evoked, on average, 54.2 ± 1.1 writhing
movements within the observation period. At the same
time, the respective value in sleep-deprived mice was
71.8 ± 2.9, i.e., about 33% greater (Fig. 2A).
Effects of Injections of Cimetidine and Atropine
were tested on separate groups of rats in the hot plate
and tail flick tests (n = 6 in all cases). Sleep deprivation
led to the development of noticeable hyperalgesia
under conditions of both thermal nociception tests.
The relative intensities of hyperalgesic shifts in these
groups differed somewhat from those observed in the
experiments described above, but the respective values
were quite comparable.
Injections of cimetidine completely removed sleep
deprivation-induced hyperalgesia in the tail-flick test
(Fig. 3B). In another thermal test, the hot plate one,
injections of this agent not only smoothed out the
shift in the sensitivity to noxious thermal stimulation
but even provided a significant analgesic effect. The
0
1
2
3
4
5
6
*
*
se c А B
F i g. 1. Diagrams of the latencies (sec) of motor defensive reactions
in the hot plate (A) and tail flick (B) tests. Open and dashed columns
show the mean ± s.e.m. values of the latencies in the control and
sleep-deprived groups, respectively. *P < 0.05 compared with the
control group.
Р и с. 1. Діаграми латентних періодів (с) моторних захисних
реакцій в тестах гарячої пластинки (А) та відсмикування хвоста
(В).
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2014.—T. 46, № 5 465
SLEEP DEPRIVATION-INDUCED HYPERALGESIA IN RODENTS
latency of defensive motor activity was in this case
more than four times longer than that in the control
group and 13 times longer than in the sleep-deprived
nontreated group (A).
Injections of atropine exerted effects parallel,
in some aspects, to those induced by cimetidine
injections. The mean latencies of responses in the
hot plate and tail withdrawal tests after introduction
of atropine were not only significantly longer than
in sleep-deprived animals with no atropine treatment
but even somewhat longer (by 21 and 36%) than the
respective values in control intact rats (Fig, 4A, B).
DISCUSSION
We observed clear hyperalgesic effects of sleep
deprivation in experiments on rats and mice. These
changes in nociception are in accordance with previous
studies on humans [4, 5] in which sleep deprivation was
found to decrease the pain thresholds. Furthermore,
F i g. 2. Diagrams of the numbers of writhings observed in the respective test (A) and durations (sec) of the paw licking in the formalin test
within the early (1) and late (2) pain phases. Other designations are the same as in Fig. 1.
Р и с. 2. Діаграми кількості «корчів» у відповідному тесті (А) та тривалості (с) лизання кінцівки у формаліновому тесті (В) у межах
ранньої (1) та пізньої (2) фаз розвитку болю.
F i g. 3. Effects of cimetidine on the hot plate (A) and tail flick (B)
normalized latencies (%) in the control (1), sleep-deprived (2), and
sleep-deprived+treated groups (3). Latencies in the control group
are taken as 100%. *P < 0.05 compared with the control; #P < 0.05
compared with the sleep-deprived group.
Р и с. 3. Впливи ціметидіну на нормовані значення (%) латентних
періодів у тестах гарячої пластинки (А) та відсмикування
хвоста (В) у контрольних (1), підданих позбавленню сну (2) та
позбавлених сну з попереднім уведенням ціметидіну (3) тварин.
F i g. 4. Effects of atropine on the hot plate (A) and tail flick (B)
normalized latencies (%) in the control (1), sleep-deprived (2), and
sleep-deprived+treated groups (3). Other designations are the same
as in Fig. 3.
Р и с. 4. Впливи атропіну на нормовані значення (%)латентних
періодів у тестах гарячої пластинки (А) та відсмикування
хвоста (В).
0
20
40
60
8 0
A
* *
*
B
0
20
40
60
8 0
100
se c
1 2
0
1 2 3 1 2 30
100
100
50
150
200
300
400
500
% %
A
A
*
*
* #
#
B
0 1 2 3 1 2 3
100
50
150
%
A
* *
*
#
#
B
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2014.—T. 46, № 5466
G. F. IBIRONKE and C. O. AJONIJEBU
the results of several animal studies also supported the
view that sleep deprivation enhances nociception [17,
18]. Our above-described findings contradict a few
previous reports that failed to identify any effect of
sleep deprivation on the pain thresholds [6, 7]. This
discrepancy is probably caused by some differences
in the study design, especially in the conditions of
sleep deprivation. We tested the effects of 24-h-long
continuous sleep deprivation in rodents, while the
authors of the contradictory findings investigated the
effects of two nights of sleep deprivation separated by
a 24-h-long recovery sleep in humans. The possibility
of some other existing factors also cannot be ruled out.
The underlying mechanisms by which sleep depri-
vation decreases pain thresholds remain mostly un-
clear. As was found [8, 9], the analgesic action of
endogenous and exogenous opioids is dependent on
undisturbed sleep architecture/continuity. Further-
more, sleep deprivation was shown to affect the se-
rotoninergic system, which plays an important role in
the pain inhibitory control [18]. These findings sug-
gest that sleep deprivation produces a transient distur-
bance of descending influences coming from the ce-
rebral pain inhibitory control systems. Our findings
showed that prior administrations of either histaminer-
gic or cholinergic receptor blockers before sleep depri-
vation practically completely smooth out deprivation-
induced hyperalgesiс shifts and can even exert some
analgesic effects. Thus, the significant roles of the his-
taminergic and cholinergic systems in the development
of sleep deprivation-induced hyperalgesia should be
taken into account. At the same time, it is obvious that
neurochemical mechanisms of such hyperalgesia need
further investigations.
The above-discribed experiments were carried out in agre-
ement with the internationally accepted ethical norms for the
works on vertebrate animals.
The authors, G. F. Ibironke and C. O. Ajonijebu, confirm that
they have no conflict of interest.
Г. Ф. Ібіронке1, К. О. Айоніджебу1
ДЕЯКІ НЕЙРОХІМІЧНІ МЕХАНІЗМИ ГІПЕРАЛГЕЗІЇ,
ВИКЛИКАНОЇ ПОЗБАВЛЕННЯМ СНУ, У ГРИЗУНІВ
1 Ібаданський Університет (Нігерія).
Р е з ю м е
Ми оцінювали впливи позбавлення сну на пороги болю,
що визначалися в термальних та хімічних ноцицептив-
них тестах. Дорослі самці щурів лінії Вістар та мишей
були рандомізовано розподілені на три групи: тварини без
депривації (контроль), піддані позбавленню сну протягом 24
год, а також піддані позбавленню сну з попереднім уведен-
ням або антагоніста гістамінових H2-рецепторів ціметидіну,
або блокатора холінергічних рецепторів атропіну. Позбав-
лення сну призводило до вірогідних зменшень латент-
них періодів моторних реакцій у тестах гарячої пластин-
ки та відсмикування хвоста, істотного збільшення кількості
«корчів» у відповідному тесті з внутрішньоочеревинним
уведенням оцтової кислоти та до вірогідного збільшення
тривалості лизання кінцівки у формаліновому тесті
(P < 0.05 у всіх випадках). Зміни індексів у всіх термаль-
них та хімічних тестах свідчили про розвиток помітної
гіпералгезії. Попередні введення ціметидину та атропіну
значною мірою усували ці прояви гіпералгезії, викликані
позбавленням сну, на що вказувало збільшення латентних
періодів захисних реакцій в обох використаних термаль-
них тестах. Отже, і гістамінергічна, і холінергічна системи
відіграють істотну роль у гіпералгезії, викликаній позбав-
ленням сну.
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