Series of Selected Papers from President's Undergraduate Research Fellowship,Peking University(2003)
Involvement of opioid receptors in the
oxytocin-induced antinociception in central
nervous system of rats
Lian Gao, Long-Chuan Yu*
Laboratory of Neurobiology, College of Life Sciences
Abstract
Recent studies showed that oxytocin and opioid peptides play important roles in
pain modulation at different levels in the central nervous system. The present
study was performed to explore whether opioid system is involved in the
oxytocin-induced antinociception in the brain of rats. The results showed that: (1)
Intracerebroventricular injection of oxytocin induced dose-dependent increases in
hindpaw withdrawal latencies (HWL) to noxious thermal and mechanical
stimulation in rats. (2) The antinociceptive effect of oxytocin was attenuated
dose-dependently by intracerebroventricular injection of naloxone, indicating an
involvement of opioid system in the oxytocin-induced antinociception. (3) It is
interesting that the antinociceptive effect of oxytocin was attenuated by
subsequent intracerebroventricular injection of the mu-opioid antagonist β
-funaltrexamine (β-FNA) and the kappa-opioid antagonist nor-binaltorphimine
(nor-BNI), but not the delta-opioid antagonist naltrindole. The results indicate that
oxytocin plays an antinociceptive role in the brain of rats, mu- and kappa-opioid
receptors, not delta-receptors, are involved in the oxytocin-induced
antinociception in the central nervous system of rats.
Key words: Oxytocin, Oxytocin receptor, Opioid receptor, lateral ventricle,
Antinociception
1. Introduction
Oxytocin (OT) is a hormone synthesized in the neurohypophysis. It has been
demonstrated that oxytocin is involved in the modulation of pain at different
levels of the central nervous system (CNS) [1-7]. Oxytocin exerts its actions via
epynomouslynamed OT receptors [8], which localize in many parts of the CNS
(cortex, olfactory system, basal ganglia, limbic system, thalamus, hypothalamus,
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Series of Selected Papers from President's Undergraduate Research Fellowship,Peking University(2003)
brain stem and dorsal horn of the spinal cord) and in the peripheral nervous
system.
Antinociceptive effect of oxytocin has been reported in many studies.
Intracerebroventricular injection of oxytocin induced antinociception [3].
Intraperitoneal or intracisternal injection of oxytocin produced antinociceptive
effect in rats or in mice [9]. Madrazo et al. found that intracerebroventricular
injection of oxytocin reduced suffering of a patient with intractable cancer pain
[10]. There is, thus, increasing interest in the role of oxytocin in antinociception.
A network of descending pathways projecting from cerebral structures to the
dorsal horn of the spinal cord plays a complex and crucial role in the transmission
of nociceptive information from the periphery to the CNS [8,11]. Oxytocin and
opioid peptides are involved in the process. Our reports demonstrated that
intra-periaqueductal gray (PAG) or nucleus raphe magnus (NRM) and
intracerebroventricular injection of oxytocin induced dose-dependent
antinociceptive effects in rats [5,7,12].
It is well known that opioid peptides play an important role in antinociception
in the brain. The efficacy of intracerebroventricular administration of morphine
has been well documented [13,14]. Also, intracerebroventricular injection of muand delta-opioid receptor agonists produced dose-dependent antinociception in the
Randall Sellito test [15] and hot-plate test [16] in rats, and in mice, the
intracerebroventricular administration of opioid receptor agonist have been shown
to produce antinociception tested by hot-plate or tail-flick [17-19]. Furthermore, it
has been demonstrated that oxytocin-induced antinociceptive effect was
attenuated by intrathecal administration of the opioid antagonist naloxone,
suggesting an involvement of the endogenous opioid system in the
oxytocin-induced antinociception at the spinal level in rats with inflammation [20].
Recent studies in our laboratory have shown that opioid receptors were involved
in the oxytocin-induced antinociception in the PAG [5] and NRM [12] of rats. The
aim of the present study was to investigate the involvement of opioid receptors in
the oxytocin-induced antinociception in the central nervous system of rats.
2. Materials and methods
2.1. Animals
All experiments were performed on freely moving male SD rats (220–250 g;
Experimental Animal Center of Henan Medical University, Henan, China). The
rats were housed in cages with free access to food and water, and maintained in a
room temperature of 25±2oC with a 12 h light–dark cycle. All experiments were
conducted according to the guidelines of the International Association for the
Study of Pain [21] and every effort was made to minimize both the animal
suffering and the number of animals used.
2.2. Chemicals
Solutions for intracerebroventricular injection were prepared with sterilized
saline (0.9%), each with a volume of 5 μl of: (1) 0.05, 0.1 or 0.25 nmol of
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Series of Selected Papers from President's Undergraduate Research Fellowship,Peking University(2003)
oxytocin (Penisula Laboratories, USA); (2) 0.1, 0.5 or 1 μg of naloxone (naloxone
hydrochloride; Sigma Chemical Company, St. Louis, MO); (3) 10 nmol of β
-funaltrexamine (β-FNA hydrochloride; Tocris, Balwin, MO 63011, USA); (4)
10 nmol of nor-binaltorphimine (nor-BNI dihydrochloride; Tocris, Balwin, MO
63011, USA); (5) 10 nmol of naltrindole (naltrindole hydrochloride; Tocris,
Balwin, MO 63011, USA).
2.3. Neuropharmacological experiment
2.3.1. Training before the operations
All rats were accustomed to the test condition for 5 days before the experiment
was carried out. After the training, the latency of hindpaw withdrawal to thermal
stimulation was about 4.5-5.5 s and to mechanical stimulation was about 5-7 s.
2.3.2. The hot-plate and Randall Selitto test
The response to noxious thermal stimulation was assessed by the hot-plate test
[22,23]. The entire ventral surface of the rat’s hindpaw was placed manually on
the hot-plate, which was maintained at a temperature of 52 oC (51.7-52.3oC). The
latencies to hindpaw withdrawal during thermal and mechanical stimulation were
measured and expressed in seconds to be referred to as the hindpaw withdrawal
latency (HWL).
The Randall Selitto Test (Ugo Basile, Type 7200, Italy) was used to assess the
HWLs to noxious mechanical stimulation [22,23]. A wedge-shaped pusher at a
loading rate of 30 g/s was applied to the dorsal surface of the manually handled
hindpaw and the latency required to initiate the withdrawal response was assessed
and expressed in seconds.
In both of the tests, 15 s was the cut-off time to prevent possible tissue damage.
The average values obtained before intracerebroventricular injection were
regarded as the basal HWL. The HWLs recorded during subsequent experiments
were expressed as percentage changes of the basal level for each rat (% changes
of the HWL). Each rat was tested with both types of stimulation.
2.3.3. Intracerebroventricular injection
The animals were anaesthetized by intraperitoneal pentobarbital (45 mg/kg) and
were mounted on a stereotaxic instrument. A stainless steel guide cannular of 0.8
mm outer-diameter was directed into the lateral ventricle (AP, -0.92 mm; LR, 1.5
mm; V, 3.6 mm from the surface of the skull. AP, anterior (+) or posterior (-) to
Bregma; L or R, left or right to midline; V, ventral to the surface of skull)
according to Paxinos and Watson [24] and was fixed to the skull by dental acrylic.
On the day of experiment, a stainless steel needle with 0.4 mm diameter was
directly inserted into the guide cannula, with 1 mm beyond the tip of the latter.
Five microliter of solution was thereafter infused into the lateral ventricle over 1
min.
2.3.4. Histologic verification of the injection site
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Series of Selected Papers from President's Undergraduate Research Fellowship,Peking University(2003)
At the end of the experiments the rat was killed by a high dose of pentobarbital
(80 mg/kg) and the rat heads were fixed in 10% formalin for 24 hours with the
injecting tube in situ before section. The location of the tip of the injecting tube
was verified and all the tips of the injecting tube were in lateral ventricle area of
rats in the present study.
2.3.5. Statistical analysis
Data from nociceptive tests were presented as mean±S.E.M. The two-way
analysis of variance (ANOVA) was used to evaluate the difference in HWLs
between two groups (Fleft/left is the F value of the two groups: the left HWL of the
first group compared with the left HWL of the second group). *P<0.05, **P<0.01
and ***P<0.001 were considered as significant differences.
3. Results
3.1. Effects of intracerebroventricular injection of oxytocin on HWLs to noxious
thermal and mechanical stimulation in rats
Rats received intracerebroventricular injection of 0.05 (n=6), 0.1 (n=6) or 0.25
nmol of oxytocin (n=6), or 5 μl of 0.9% saline as a control (n=8). As shown in Fig.
1, the HWLs to thermal and mechanical stimulation increased significantly after
intracerebroventricular injection of 0.25 nmol of oxytocin (Thermal test:
Fleft/left=26.17, P<0.001; Fright/right=59.26, P<0.001; Randall Selitto test:
Fleft/left=38.72, P<0.001; Fright/right=14.58, P<0.01), but not 0.1 nmol of oxytocin
(Thermal test: Fleft/left=4.16, P=0.06; Fright/right=0.68, P=0.43; Randall Selitto test:
Fleft/left=8.03, P<0.05; Fright/right=2.09, P=0.17), or 0.05 nmol of oxytocin (Thermal
test: Fleft/left=1.01, P ＝ 0.33; Fright/right=0.26, P=0.62; Randall Selitto test:
Fleft/left=0.36, P=0.56; Fright/right=0.13, P=0.72), compared with the control group.
The HWLs increased and to reach the peak at 10 min after intracerebroventricular
injection of oxytocin, and then recovered to the basal line at 30 min.
3.2. Blockade effects of intracerebroventricular injection of naloxone on the
oxytocin-induced increase in HWLs
Rats received intracerebroventricular injection of 0.25 nmol of oxytocin,
followed 5 min later by intracerebroventricular administration of 0.1 (n=6), 0.5
(n=6) or 1 μg of naloxone (n=6), or 5 μl of 0.9% saline as a control (n=6). The
results are shown in Fig. 2. Compared with the control group, the increased
HWLs to thermal stimulation were attenuated significantly after administration of
1 μg (Fleft/left=21.26, P <0.001; Fright/right=38.23, P<0.001) and 0.5 μg of naloxone
(Fleft/left=12.23, P<0.01; Fright/right=9.50, P<0.05), but not 0.1 μg of naloxone
(Fleft/left=0.01, P=0.91; Fright/right=0.76, P＝0.40) compared to the control group.
And the increased HWLs to mechanical stimulation were also attenuated
significantly after administration of 1 μg of naloxone (Fleft/left=15.97, P<0.01;
Fright/right=15.46 P< 0.01), but not 0.5 μg (Fleft/left=1.86, P=0.20; Fright/right=1.78,
P=0.21) and 0.1 μg of naloxone (Fleft/left=3.00, P＝0.11; Fright/right=1.33, P＝0.27)
compared with the control group. Another group of rats (n=6) received
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Series of Selected Papers from President's Undergraduate Research Fellowship,Peking University(2003)
intracerebroventricular injection of 5 μl of 0.9% saline, followed 5 min later by 1
μg of naloxone. There were no marked changes in HWLs during 30 min after the
injection.
3.3. Influence of different opioid antagonists on the oxytocin-induced increase in
HWLs
Rats received intracerebroventricular administration of 0.25 nmol of oxytocin,
followed 5 min later by 10 nmol of β-FNA (n=6), 10 nmol of nor-BNI (n=6) or
10 nmol of naltrindole (n=6), or 5 μl of 0.9% saline as a control (n=6). The results
are shown in Fig. 3. Compared with the control group, the increased HWLs to
both thermal and mechanical stimulation were attenuated significantly after
administration of 10 nmol of β-FNA (Thermal test: Fleft/left=16.05, P<0.01;
Fright/right=43.98, P<0.001; Randall Selitto test: Fleft/left=24.72, P<0.001;
Fright/right=14.43, P<0.01) and 10 nmol of nor-BNI (Thermal test: Fleft/left=52.17,
P<0.001; Fright/right=146.81, P<0.001; Randall Selitto test: Fleft/left=13.34, P<0.01;
Fright/right=21.82, P<0.001), but not 10 nmol of naltrindole (Thermal test:
Fleft/left=0.87, P=0.37; Fright/right=0.03, P=0.87; Randall Selitto test: Fleft/left=0.30,
P=0.60;
Fright/right=0.04, P=0.84).
Two groups
of rats
received
intracerebroventricular injection of 5 μl of 0.9% saline, followed 5 min later by 10
nmol of β-FNA (n=6) or nor-BNI (n=6). There were no marked changes in
HWLs during 30 min after the injection.
4. Discussion
The present study showed that intracerebroventricular injection of oxytocin
increased the rat’s pain threshold, and the increase in induced HWLs to both
thermal and mechanical stimulation was about 40% by 0.25 nmol of oxytocin and
about 20% by 0.1 nmol of oxytocin (Fig. 1). It demonstrated that oxytocin played
a dose-dependent antinociceptive effect in the brain of rats. Arletti et al. found that
intracerebroventricular injection of oxytocin increased the latencies of rat’s
tail-flick, what could be reversed by the selective oxytocin antagonist [3]. The
result demonstrated that the antinociceptive effect of oxytocin in the lateral
ventricle has respect to oxytocin receptors, and indicated that oxytocin activate
oxytocin receptors in the brain to modulate the nociceptive response. When high
dose (10 nmol/rat) of oxytocin was used, 5-10 min after injection, rats would
become paralyzed and kept barrel rotating [3]. In present study, rats were mild
insane for hours after intracerebroventricular injection of 1 nmol of oxytocin,
which could also increase the HWLs by about 50%. The result may be impact by
both the antinociception of oxytocin and the nonspecific epilepsia, in view of that,
present study use a relatively low dose, 0.25 nmol of oxytocin to minimize the
influence of insanity to the thermal and mechanical test. Studies showed that in
the central nervous system, the oxytocin gene is primarily expressed in
magnocellular neurons in the hypothalamic paraventricular nucleus and supraoptic
nucleus [25]. Action potentials in these neurosecretory cells trigger the release of
oxytocin from their axon terminals in the neurohypophysis [26]. Also, studies
showed that oxytocin fibers and endings have been described in nuclei around the
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Series of Selected Papers from President's Undergraduate Research Fellowship,Peking University(2003)
lateral ventricle of rats [25].
It is well known that opioid peptides play a key role in antinociception in the
central nervous system [8,27,28]. Intracerebroventricular injection of opioid
peptides produced dose-dependent antinociception [13-19]. Previous studies
showed that oxytocin-induced antinociception could be blocked by the
non-selective opioid receptor antagonist naloxone in the supraspinal level [3]. In
the present study, same result was found that the oxytocin-induced increases in
HWLs were attenuated significantly by administration of non-selective opioid
antagonist naloxone (Fig. 2), indicating an involvement of opioid system in the
process of nociceptive modulation of oxytocin in the brain. It is well known that
there are three types of opioid receptors in the rat central nervous system, mu-,
delta- and kappa-opioid receptors [29-31]. Interestingly, the oxytocin-induced
antinociceptive effect to both thermal and mechanical stimulation were blocked
significantly by intracerebroventricular administration of 10 nmol of β-FNA or
nor-BNI, the antagonist of mu- and kappa-opioid receptors, but not the antagonist
of delta-opioid receptors naltrindole (Fig. 3), indicating that mu- and kappa-opioid
receptors, not delta0opioid receptor, are involved in the oxytocin-induced
antinociception in the brain.
The hot-plate and the Randall Sellito test were used to assess the effect of
antinociception in the present study. According to our results, it seems that the
oxytocin-induced increase of HWLs to thermal stimulation was more significant
than that to mechanical stimulation. Whether oxytocin has more effect on
thermal-sensor than pressure-sensor remains to be determined.
Taken together, the present study demonstrated that oxytocin plays an
antinociceptive role in the brain of rats, mu- and kappa-opioid receptors, not
delta-receptors, are involved in the oxytocin-induced antinociception in the central
nervous system of rats.
Acknowledgements
This study was supported by the President's Undergraduate Research
Fellowship (PURF), Peking University and funds from the National Natural
Science Foundation of China (NSFC). Thanks to my advisor, Professor Yu, and all
my workmates in my laboratory.
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%Changes of HWL to
thermal stimulation
60
OT 0.25 nmol
OT 0.1 nmol
OT 0.05 nmol
Saline
50
40
30
20
10
0
***
***
***
*
**
-10
%Changes of HWL to
mechanical stimulation
-20
40
30
20
10
0
-10
0
5
10
15
20
25
min
30
0
5
10
15
20
25
30
Fig. 1. Effects of intracerebroventricular administration of oxytocin on HWLs to thermal (A
and B) and mechanical stimulation (C and D) in rats. Left HWL: A and C; right HWL: B and
D. Time=0 min: intracerebroventricular injection of 0.05, 0.1 or 0.25 nmol of oxytocin, or 5
μl of 0.9% saline as the control group. Data are presented as mean  S.E.M, % change of
HWL (vertical axis). Horizontal axis indicates minutes (min) after the injection. The statistical
difference between groups was evaluated by two-way ANOVA. OT, oxytocin; HWL, hindpaw
withdrawal latency. *P<0.05, **P<0.01 and ***P<0.001 compared with the control group.
9
min
Series of Selected Papers from President's Undergraduate Research Fellowship,Peking University(2003)
%Changes of HWL to
thermal stimulation
70
OT 0.25 nmol + Saline 5 l
OT 0.25 nmol + NX 1 g
OT 0.25 nmol + NX   g
OT 0.25 nmol + NX  1 g
Saline 5 l + NX 1 g
60
50
40
30
20
10
0
***
**
***
*
**
**
%Changes of HWL to
mechanical stimulation
-10
50
40
30
20
10
0
-10
0
5
10
15
20
25
min
30
0
5
10
15
20
25
30
Fig. 2. Inhibitory effects of intracerebroventricular administration of naloxone on the
oxytocin-induced increases in HWLs to thermal (A and B) and mechanical stimulation (C and D)
in rats. Left HWL: A and C; right HWL: B and D. Time=0 min: intracerebroventricular
administration of 0.25 nmol of oxytocin; Time=5 min: intracerebroventricular administration of
0.1, 0.5 or 1 μg of naloxone, or 5 μl of 0.9% saline as the control group. Data are presented
as mean  S.E.M, % change of HWL (vertical axis). Horizontal axis indicates minutes (min)
after the injection. The statistical difference between groups was evaluated by two-way ANOVA.
OT, oxytocin; NX, naloxone; HWL, hindpaw withdrawal latency. *P<0.05, **P<0.01 and
***P<0.001 compared with the control group.
10
min
Series of Selected Papers from President's Undergraduate Research Fellowship,Peking University(2003)
%Changes of HWL to
thermal stimulation
60
OT 0.25 nmol + Saline 5 l
OT 0.25 nmol +  -FNA 10 nmol
OT 0.25 nmol + nor-BNI 10 nmol
OT 0.25 nmol + naltrindole 10 nmol
50
40
30
20
10
0
**
***
***
***
***
**
**
***
%Changes of HWL to
mechanical stimulation
-10
40
30
20
10
0
-10
0
5
10
15
20
25
min
30
0
5
10
15
20
25
30
Fig. 3. Influence of intracerebroventricular administration of β-FNA, nor-BNI and naltrindole
on the oxytocin-induced increases in HWLs to thermal (A and B) and mechanical stimulation (C
and D) in rats. Left HWL: A and C; right HWL: B and D. Time=0 min: intracerebroventricular
administration of 0.25 nmol of oxytocin; Time=5 min: intracerebroventricular administration of
10 nmol of β-FNA, nor-BNI or naltrindole, or 5 μl of 0.9% saline as the control group. Data
are presented as mean  S.E.M, % change of HWL (vertical axis). Horizontal axis indicates
minutes (min) after the injection. The statistical difference between groups was evaluated by
two-way ANOVA. OT, oxytocin; β-FNA, β-funaltrexamine; nor-BNI, nor-binaltorphimine;
HWL, hindpaw withdrawal latency. *P<0.05, **P<0.01 and ***P<0.001 compared with the
control group.
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min
Series of Selected Papers from President's Undergraduate Research Fellowship,Peking University(2003)
作者简介：
高炼，女，1982 年 2 月出生于湖南长沙，2000 年从湖南师范大学附属中学
考入北京大学生命科学学院。在校期间学习刻苦努力，成绩优异，热心班级事务，
积极参与班上组织的各项活动，思想品德优秀，尊敬师长，人际关系良好。
2002 年进入于龙川教授的神经生物学实验室，从事神经递质，神经肽在大
鼠中枢神经系统中的痛觉调制作用的研究，取得了很多实验成果，部分工作结果
已作为合作者整理成文，投国外高水平刊物。
感悟与寄语：
能获得校长基金的资助，我觉得非常荣幸，作为一个本科生，能有这样的机
会，做科研，写论文，我觉得这是一笔难得的财富，这也得益于老师们对我的培
养，以及实验室的同学们对我的帮助，我的收获不仅仅是几篇论文，而且是一种
科学思考，不断进取的精神，这些都是我努力奋进，取得成果的动力。
在实验的过程中，我学到了很多书本上学不到的知识和技能，锻炼了自己独
立学习和科研的能力，为我以后的学习和工作打下了坚实的基础。
在此，我再次对关心和帮助我的老师和同学表示衷心的感谢。
指导教师简介：
于龙川，男，北京大学生命科学学院教授，博士生导师，北京大学生命科学
学院神经生物学实验室负责人。获博士学位（北医大，1987）和医学科学博士学
位（瑞典 Karolinska 研究院，1998）。1995 年 11 月回国并组建神经生物学研究
室，研究神经肽及其受体在中枢神经系统内对痛觉信息传递的调节作用，阿片耐
受和依赖的神经机制，以及神经肽及其受体在早老年性痴呆(Alzheimer’s Disease)
发病机理及预防和治疗中的作用。自 95 年以来在国外较高水平的学术杂志发表
科研论文约 40 篇。
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