The antinociceptive role of central arginine vasopressin is involved in the endogenous opiate peptide, serotonin and acetylcholine systems

doi:10.4236/wjns.2011.13008

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World Journal of Neuroscience, 2011, 1, 49-54

doi:10.4236/wjns.2011.13008 Published Online November 2011 (http://www.SciRP.org/journal/wjns/

WJNS

Published Online November 2011 in SciRes. http://www.scirp.org/journal/WJNs

The antinociceptive role of central arginine vasopressin is

involved in the endogenous opiate peptide, serotonin and

acetylcholine systems

Xiang-Yong Li1,2, Jun Yang1*, Xi-Qing Yan1, Yan-Juan Pan1, Ying Zhao1, Pei-Yong Qiu1, Xi-Jian Zhou2,

Da-Xin Wang3

1College of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China;

2101 Hospital of PLA, Wuxi, Jiangsu, China;

3Jiangsu Su Bei People’s Hospital, Yangzhou University, Yangzhou, Jiangsu, China.

Email: *[email protected]

Received 19 August 2011; revised 5 October 2011; accepted 24 October 2011.

ABSTRACT

Our previous work has demonstrated that arginine

vasopressin (AVP) plays a role in pain modulation.

The present study investigated which kinds of neu-

ropeptides and neurotransmitters in central nervous

system might be involved in AVP antinociceptive role

in the rat. The results showed that (1) intraventricu-

lar injection (icv) of V1 receptor antagonist [d(CH2)5-

Tyr(Me)AVP] and V2 receptor antagonist [d(CH2)5-

[D-Ile2, Ile4, Ala9-NH2]AVP] blocked the antinocicep-

tive effect induced by AVP (icv), (2) the opiate recap-

tor antagonist (naloxone) reversed the antinociceptive

effect induced by AVP (icv), and (3) both the sero-

tonin receptor antagonist (cypoheptadine) and M re-

ceptor antagonist (atropine) could attenuate the anti-

nociceptive effect induced by AVP (icv); but (4) oxyto-

cin, dopamine, N-methyl-D-aspartate (NMDA), γ-amino-

butyric acid (GABA), N, α or β receptor antagonist

did not influence the antinociceptive effect induced

by AVP (icv). The data suggested that AVP antinoci-

ceptive role was involved in the endogenous opiate

peptide, serotonin and acetylcholine systems in cen-

tral nervous system.

Keywords: Arginine Vasopressin; Antinociception; En-

dorgenous Opiate Peptide; Serotonin; Acetycholine

1. INTRODUCTION

Arginine vasopressin (AVP), a nonapeptide posterior pi-

tuitary hormone, is synthesized in the paraventricular and

supraoptic nuclei of hypothalamus [1]. This hormone,

combined with an apparent carrier protein (neurophysin),

is transported along the hypothalamo-hypophyseal pathway

to the neurohypophysis, where it is stored for subsequent

release [2]. The remarkable functions of AVP include body

fluid homeostasis, hormone probation, cardiovascular con-

trol, learning and memory [3]. Many studies have showed

that AVP influences antinociception in both human and

nonhuman species [1,4-7]. Intraventricular injection (icv)

of AVP increases the pain threshold, while anti-AVP se-

rum (icv) decreases the pain threshold, but intrathecal

injection (ith) or intravenous injection (iv) of either AVP

or anti-AVP serum does not influence the pain threshold

[8,9]. Pain stimulation could change AVP concentration

in some brain nuclei, but did not change AVP concentra-

tion in the spinal cord and serum [8,9]. The antinocicep-

tive effect of AVP is limited to the brain nuclei, not the

spinal cord and peripheral organs.

Many studies have proven that most of neuropeptides

(such as endogenous opiate peptides) and neurotransmit-

ters (such as serotonin, acetylcholine, norepinephine and

epinephrine) are involved in pain modulation [10]. For

example, oxytocin (icv) could increase the pain threshold

and enhance acupuncture analgesia, while anti-oxytocin

serum (icv) decreases the pain threshold and weakens

acupuncture analgesia [11-13]. However, it is not clear

the interaction between AVP and other neuropeptides or

neurotransmitters in pain modulation. The present study

investigated which neuropeptides and neurotransmitters

in central nerve system might be involved in AVP anti-

nociceptive effect in the rat.

2. MATERIALS AND METHODS

2.1. Animals

Adult male Sprague-Dawley rats weighing 180-220 g,

which were obtained from Animal Center of Yangzhou

University, Yangzhou, Jiangsu, China, were housed with

food and water available ad libitum in a colony room

under controlled temperature, humidity and a 12 hours

X.-Y. Li et al. / World Journal of Neuroscience 1 (2011) 49-54

light/dark cycle (light at 6:00 AM and dark at 6:00 PM).

All the procedures were approved by Animal Care Com-

mittee of Yangzhou University and conducted according

to the guidelines of the International Association for the

Study of Pain [14].

2.2. Materials

AVP, d(CH2)5Tyr(Me)AVP, d(CH2)5[D-Ile2, Ile4, Ala9-

NH2]AVP and [1-D(CH2)5,Tyr(ME)2,Thr4,Tyr-NH2(9)]

ornithine vasotocin were obtained from Peninsula Lab,

San Carlos, CA, USA. Naloxone, cypoheptadine, atropine,

6-OH gallamine, fluperidol, phentolamine, propranolol,

MK801, bicuculline, 5-amino valeric acid (5AVA), 3-ami-

noproyl phossphonic acid (3APPA). and the other chemi-

cals were bought from Sigma Co., St. Louis, MO, USA.

2.3. Surgery

With Pellegrino L.J. rat brain atlas as reference, we used

the stereotaxic apparatus (Jiangwan I-C, Shanghai, China)

to implant a stainless steel guide cannula of 0.5 mm outer

diameter into the right lateral ventricle (AP 0.3 mm, LR

0.5 mm, H 3.0 mm) for icv under the pentobarbital so-

dium (35 mg/kg, intraperitoneal injection) anaesthesia.

The guide cannula was fixed to the skull by dental acrylic.

All operations were carried out in the aseptic condition

and the animals were allowed to recover for at least 14

days after the surgery.

2.4. Intraventricular Injection (Icv)

On the day of experiment, a stainless steel needle with

0.3 mm diameter for icv was directly inserted into the guide

cannula, with 1mm beyond the tip of the latter. The 10

ml of antiserum or solution was injected into the lateral

ventricle gently over 10 min.

2.5. Nociceptive Tests

All animals were tested under the condition of free ac-

tivity in the small cages (30 cm in diameter, 25 cm in

height) from 8:00 to 10:00 am. Depending on the 30-year

experience of studying pain in our laboratory, we used

the potassium iontophoresis inducing tail-flick served as

pain stimulus. The small wet cotton with the potassium

iontophoresis was set on the skin of the tail. The cotton

was exposed to direct electrical current, and the anode

led the potassium iontophoresis to permeate the skin of

the tail. If the current was strong enough, the permeated

potassium iontophoresis resulted in the animal feeling

the pain stimulation. The intensity of current at the mo-

ment of the response was recorded as the pain threshold,

which was expressed as mA (WQ-9E Pain Threshold

Measurer, Shanghai, China). The duration between con-

secutive stimuli was 10 min, and the pain stimulus was

terminated at once when the rat showed response to this

stimulus.

2.6. Histological Verification

At the end of the experiments, the rat was sacrificed un-

der the high dose of pentobarbital sodium (80 mg/kg, in-

traperitoneal injection), and the histological location of

icv was ascertained. The data were excluded from analy-

sis if the positions were not accurate.

2.7. Statistical Analysis

All values were expressed as mean ± standard error of

the mean (SEM) and were analyzed between groups by

analysis of variance (ANOVA) and χ2 test. P < 0.05 was

considered statistically significant.

3. RESULTS

3.1. Effect of the Neuropeptide Receptor

Antagonist on Pain Threshold Increase

Induced by AVP (icv)

Table 1 showed that 100 ng AVP (icv) could increase the

pain threshold from 0.52 ± 0.03 mA to 0.77 ± 0.04 mA

(P < 0.001).

Although icv of 2 μg d(CH2)5Tyr(Me)AVP (V1 recep-

tor antagonist), 2 μg d(CH2)5[D-Ile2, Ile4, Ala9-NH2]AVP

(V2 receptor antagonist), 2 μg [1-D(CH2)5,Tyr(ME)2,Thr4,

Tyr-NH2(9)] ornithine vasotocin (oxytocin receptor an-

tagonist) or 2 μg naloxone (opiate receptor antagonist)

decreased the pain threshold (all p < 0.01 ~ 0.001), ven-

tricular pretreatment with V1 receptor antagonist, V2 re-

ceptor antagonis, opiate receptor antagonist could reverse

the antinociceptive effect induced by 100 ng AVP ad-

ministration (icv), and ventricular pretreatment with oxy-

tocin receptor antagonist did not influence the antino-

ciceptive effect induced by 100 ng AVP administration

(icv) (Table 1).

3.2. Effect of the Neurotransmitter Receptor

Antagonist on Pain Threshold Increase

Induced by AVP (icv)

Table 2 showed that icv of 2 μg 5-HT receptor antago-

nist (cypoheptadine), 2 μg M receptor antagonist (atro-

pine), 2 μg N receptor antagonist (6-OH gallamine), 2 μg

α receptor antagonist (phentolamine) or 2 μg β receptor

antagonist (propranolol) decreased the pain threshold (all

p < 0.01 ~ 0.001), but icv of 2 μg dopamine receptor an-

tagonist (fluperidol), 2 μg N-methyl-D-aspartate (NMDA)

receptor antagonist (MK801), 2 μg γ-aminobutyric acid

(GABA)a receptor antagonist (bicuculline), 2 μg GABAb

receptor antagonist (5-amino valeric acid) or 2 μg GABAc

receptor antagonist (3-aminoproyl phossphonic acid) did

not influence the pain threshold.

Pretreatment with either 5-HT receptor antagonist or M

receptor antagonist (icv) could attenuate the antinociceptive

X.-Y. Li et al. / World Journal of Neuroscience 1 (2011) 49-54 51

Table 1. Effect of neuropeptide receptor antagonist (icv) on the pain threshold increase induced by the central AVP.

Treatment n Before injection After 1st injection After 2nd injection

ACSF + ACSF 10 0.50 ± 0.03 0.51 ± 0.02 0.52 ± 0.03

ACSF + AVP 10 0.51 ± 0.03 0.52 ± 0.04 0.77 ± 0.04111 222 ***

V1receptor antagonist + ACSF 10 0.49 ± 0.03 0.41 ± 0.041 0.46 ± 0.04

V1receptor antagonist +AVP 10 0.51 ± 0.04 0.40 ± 0.0311 °°° 0.49 ± 0.04111 2 °°°

V2receptor antagonist + ACSF 10 0.51 ± 0.03 0.41 ± 0.02111 ** 0.43 ± 0.0311 *

V2receptor antagonist +AVP 10 0.50 ± 0.02 0.40 ± 0.02111 °°° 0.45 ± 0.021 °°°

OXT receptor antagonist + ACSF 9 0.49 ± 0.03 0.39 ± 0.0311 *** 0.41 ± 0.041 **

OXT receptor antagonist + AVP 9 0.51 ± 0.03 0.40 ± 0.03111 °°° 0.74 ± 0.0411 222 aaa

Opiate receptor antagonist + ACSF 10 0.54 ± 0.04 0.37 ± 0.01111 *** 0.35 ± 0.03111 ***

Opiate receptor antagonist + AVP 10 0.50 ± 0.02 0.34 ± 0.03111 °°° 0.62 ± 0.0311 222 °°° aaa

ACSF, 10 μl artificial cerebrospinal fluid; AVP, 100 ng arginine vasopressin; V1 receptor antagonist, 2 μg d(CH2)5Tyr(Me)AVP; V2 receptor antagonist, 2 μg

d(CH2)5[D-Ile2, Ile4, Ala9-NH2]AVP; OXT (oxytocin) receptor antagonist, 2 μg [1-D(CH2)5,Tyr(ME)2,Thr4,Tyr-NH2(9)] ornithine vasotocin; Opiate receptor

antagonist, 2 μg naloxone. All values are expressed as mean ± standard error of the mean (SEM). The unit was mA. N indicates the animal number of the group.

Before injection denotes the animal before the treatment; First injection denotes the animal given first intraventricular injection (icv) of ACSF or receptor an-

tagonist; Second injection denotes the animal given second icv of ACSF or AVP in 10 min after first injection. P < 0.05, ** P < 0.01 and *** P < 0.001 are for

the comparison of the pain threshold from marked group and ACSF + ACSF group; ° P < 0.05, °° P < 0.01 and °°° P < 0.001 are for the comparison of the pain

threshold from marked group and ACSF + AVP group; 1 P < 0.05, 11 P < 0.01 and 111 P < 0.001 are for the comparison of the pain threshold from marked value

and the value before injection; 2 P < 0.05, 22 P < 0.01 and 222 P < 0.001 are for the comparison of the pain threshold from marked value after 1st injection and the

value after 2nd injection; ªªª P < 0.001 is for the comparison of the pain threshold from receptor antagonist + AVP group and receptor antagonist + ACSF group

(corresponding control group).

Table 2. Effect of classical neurotransmitter receptor antagonists (icv) on the pain threshold increase induced by the central AVP.

Treatment n Before injection After 1st injection After 2nd injection

ACSF + ACSF 10 0.50 ± 0.03 0.51 ± 0.02 0.52 ± 0.03

ACSF + AVP 10 0.51 ± 0.03 0.52 ± 0.04 0.77 ± 0.04111 222 ***

5-HT receptor antagonist + ACSF 10 0.52 ± 0.03 0.27 ± 0.02111 *** 0.23 ± 0.01111***

5-HT receptor antagonist + AVP 10 0.47 ± 0.03 0.30 ± 0.03111 °°° 0.31 ± 0.05111 °°°

M receptor antagonist + ACSF 9 0.50 ± 0.03 0.30 ± 0.02111 *** 0.29 ± 0.02111***

M receptor antagonist + AVP 9 0.51 ± 0.03 0.33 ± 0.02111 °°° 0.60 ± 0.04111 222 °°° aaa

N receptor antagonist + ACSF 9 0.48 ± 0.03 0.47 ± 0.03 0.49 ± 0.03

N receptor antagonist + AVP 9 0.49 ± 0.03 0.50 ± 0.04 0.84 ± 0.06111 222 aaa

DA receptor antagonist + ACSF 9 0.52 ± 0.03 0.52 ± 0.04 0.51 ± 0.03

DA receptor antagonist + AVP 9 0.52 ± 0.03 0.51 ± 0.03 0.82 ± 0.05111 222 aaa

α receptor antagonist + ACSF 9 0.48 ± 0.03 0.38 ± 0.031 *** 0.33 ± 0.0411 ***

α receptor antagonist + AVP 9 0.49 ± 0.03 0.37 ± 0.031 °°° 0.81 ± 0.06111 222 aaa

β receptor antagonist + ACSF 9 0.47 ± 0.04 0.38 ± 0.031 *** 0.36 ± 0.041 ***

β receptor antagonist + AVP 9 0.48 ± 0.03 0.39 ± 0.0311 °°° 0.78 ± 0.05111 222 aaa

NMDA receptor antagonist + ACSF 8 0.51 ± 0.03 0.49 ± 0.04 0.50 ± 0.03

NMDA receptor antagonist + AVP 8 0.50 ± 0.03 0.48 ± 0.03 0.76 ± 0.05111 222 aaa

GABAa receptor antagonist + ACSF 9 0.52 ± 0.03 0.49 ± 0.03 0.48 ± 0.04

GABAa receptor antagonist + AVP 9 0.50 ± 0.04 0.52 ± 0.03 0.82 ± 0.05111 222 aaa

GABAb receptor antagonist + ACSF 9 0.48 ± 0.03 0.50 ± 0.04 0.47 ± 0.04

GABAb receptor antagonist + AVP 9 0.50 ± 0.04 0.49 ± 0.03 0.79 ± 0.05111 222 aaa

GABAc receptor antagonist + ACSF 9 0.51 ± 0.03 0.50 ± 0.03 0.47 ± 0.04

GABAc receptor antagonist + AVP 9 0.50 ± 0.04 0.52 ± 0.03 0.83 ± 0.05111 222 aaa

ACSF, 10 μl artificial cerebrospinal fluid; AVP, 100 ng arginine vasopressin; 5-HT (serotonin) receptor antagonist, 2 μg cypoheptadine; M receptor antagonist,

2 μg atropine; N receptor antagonist, 2 μg 6-OH gallamine; DA (dopamine) receptor antagonist, 2 μg fluperidol; α receptor antagonist: 2 μg phentolamine; β

receptor antagonist: 2 μg propranolol; NMDA (N-methyl-D-aspartate) receptor antagonist: 2 μg MK801; GABAa (γ-aminobutyric acid) receptor antagonist: 2

μg bicuculline; GABAb receptor antagonist: 2 μg 5-amino valeric acid (5AVA); GABAc receptor antagonist, 2 μg 3-aminoproyl phossphonic acid (3APPA).

All values are expressed as mean ± standard error of the mean (SEM). The unit was mA. N indicates the animal number of the group. Before injection denotes

the animal before the treatment; First injection denotes the animal given first intraventricular injection (icv) of ACSF or receptor antagonist; Second injection

denotes the animal given second icv of ACSF or AVP in 10 min after first injection. P < 0.05, ** P < 0.01 and *** P < 0.001 are for the comparison of the pain

threshold from marked group and ACSF + ACSF group; ° P < 0.05, °° P < 0.01 and °°° P < 0.001 are for the comparison of the pain threshold from marked

group and ACSF + AVP group; 1 P < 0.05, 11 P < 0.01 and 111 P < 0.001 are for the comparison of the pain threshold from marked value and the value before

injection; 2 P < 0.05, 22 P < 0.01 and 222 P < 0.001 are for the comparison of the pain threshold from marked value after 1st injection and the value after 2nd

injection; ªªª P < 0.001 is for the comparison of the pain threshold from receptor antagonist + AVP group and receptor antagonist + ACSF group (corresponding

control group).

X.-Y. Li et al. / World Journal of Neuroscience 1 (2011) 49-54

effect induced by 100 ng AVP administration (icv) (all P

< 0.001), but the other studied neurotransmitter recap-

tor antagonists did not influence the antinociceptive ef-

fect induced by the administration of 100 ng AVP (icv)

(Table 2).

4. DISCUSSION

AVP is synthesized within cells located in the brain and

in certain peripheral organs of the body. In the brain,

AVP is synthesized in cell groups within the hypothala-

mus; several of these cell groups release hormones into

the systemic circulation or into the portal circulation of

the anterior pituitary gland and others release neurotran-

smitters at synaptic targets within the brain. AVP is also

synthesized in certain extrahypothalamic brain sites, such

as limbic system structures in the forebrain. In peripheral

tissues, there is evidence that AVP is synthesized in the

anterior pituitary, adrenal, and thymus glands and in male

and female reproductive structures (ovaries, uterus, and

testes) [3]. However, most of AVP is synthesized in hy-

pothalamic paraventricular nucleus (PVN) and hypotha-

lamic supraoptic nucleus (SON) [2,15]. It has been proven

that PVN and SON play an important role in analgesia

[16-20], and AVP, which may be from PVN and SON, is

involved in pain modulation [21,22].

Our present study showed that (1) not only V1 recep-

tor antagonist [d(CH2)5Tyr(Me)AVP] and V2 receptor

antagonist [d(CH2)5[D -Ile2, Ile4, Ala9-NH2]AVP] blocked

the antinociceptive effect induced by AVP (icv), but also

the opiate receptor antagonist (naloxone), 5-HT receptor

antagonist (cypoheptadine) and M receptor antagonist

(atropine) could reserve the antinociceptive effect in-

duced by AVP (icv); (2) oxytocin, dopamine, NMDA,

GABA, N, α and β receptor antagonist did not influence

the antinociceptive effect induced by AVP (icv). The data

suggested that AVP antinociceptive effect was related

with the endogenous opiate peptide, serotonin and ac-

erycholine systems.

Histological study has shown that there are many AVP

containing fibers in the periaqueductal gray (PAG), which

come from PVN neurons [23,24]. AVP enhances the syn-

thesis and secretion of endogenous opiate peptides in the

PAG [25,26].

The nucleus raphe magnus (NRM) is a serotonergic

nucleus located in the rostral ventromedial medulla of

the brainstem. Axons of the NRM project to the spinal

cord [27], terminating primarily in the dorsal horn [28].

Brainstem nuclei that project to the dorsal horn of the

spinal cord can function to inhibit afferent nociceptive

transmission [29-31]. Activation of these descending an-

tinociceptive pathways may be triggered by physiologi-

cal stimuli [32] as well as by pharmacological agents [33].

Antinociception involving the NRM has been studied

after either electrical stimulation or direct administration

of pharmacological agents [34-36]. The NRM is a key

neural structure for pain modulation, in which serotonin

(5-HT) is a major site for pain regulation [10]. AVP and

5-HT interaction in the brain controls many animal be-

haviors [37,38].

There are many bioactive substances in the caudate

nucleus (CdN) including dopamine (DA) and acetylcho-

line (Ach), which show interaction with AVP [35,39-41].

DA and Ach in CdN are important bioactive substances

in pain modulation and the CdN is showing an important

neural structure in pain modulation [38].

Our pervious study has shown that AVP in the PAG,

NRM and CdN could regulate the pain process [18,42,43],

and pain stimulation changes the AVP concentration in

the PAG, NRM and CdN [15,40]. So we could imagine

that AVP regulating the pain process might be involved

in the endogenous opiate system in the PAG, serotonin

system in the NRM and acetylcholine system in the CdN.

However, it needs to be confirmed.

5. ACKNOWLEDGEMENTS

This work was supported by Xinxiang Medical University, 101 Hospi-

tal of PLA, Jiangsu Su Bei People’s Hospital and grants from National

Basic Research Program of China (2007CB936104).

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