Neuropeptides(1998)32 (6), 543-548
© HarcourtBrace & Co. Ltd 1998
Sensory s t i m u l a t i o n ( a c u p u n c t u r e )
i n c r e a s e s the r e l e a s e of v a s o a c t i v e
intestinal p o l y p e p t i d e in the saliva of
x e r o s t o m i a sufferers
I. Dawidson ~, B. Angmar-M&nsson ~, M. Blom ~, E. Theodorsson 2, "r. Lundeberg 3
1Department of Cariology, Karolinska Institutet, Box 4064, 141 04 Huddinge, Sweden
2Clinical Chemistry, University Hospital, Link6ping, Sweden
3Departments of Physiology and Pharmacology and Surgery and Rehabilitation, Karolinska Institutet, 104 01 Stockholm, Sweden
Summary We have shown in earlier studies that xerostomia can be treated successfully with acupuncture. We also
found that acupuncture stimulation can increase the concentration of neuropeptides in the saliva of healthy' subjects, in
this study, the concentration of the neuropeptide vasoactive intestinal polypeptide (VIP) was measured in the saliva of
xerostomic patients in connection with acupuncture treatment (AP). Patients suffering from xerostomia caused by
irradiation treatment, SjSgren's syndrome and other systemic disorders had been treated with acupuncture. Some of
these patients showed an increase of their salivary flow rates after the AP was completed. Seventeen patients out of 65
were chosen due to their ability to produce enough saliva for the radio immunoassay (RIA) analyses to be conducted prior
to the start of AP. VIP-like immunoreactivity (VIP-LI) was measured in the chewing stimulated saliva of these patients
before and after the whole AP (24 sessions of 30 min each). The results showed that there was a significant increase of
the concentration of VIP after the AP as compared to the measurements made before the start of the treatment (p<0.05).
We concluded that the increase of neuropeptide VIP might be one of the mechanisms behind the positive effect of
acupuncture on the salivary flow rates of the xerostomic patients.
INTRODUCTION
An insufficient production of saliva is an extremely
unpleasant symptom of several systemic diseases, of
which primary and secondary Sj6gren's syndrome are the
most common. The salivary glands of xerostomia sufferers become severely impaired by chronic inflammatory
process. I-3 Patients who have been treated with radiation
therapy for head and neck tumours are similarly
afflicted. 4 Several patients suffering from xerostomia
have been treated with acupuncture over the last decade.
The results of those studies showed that the salivary flow
rates of many of these patients increased after the treatment and the positive results persevered during a long
observation period. 5-z The functions of the salivary
Received 3 July 1998
Accepted 13 August 1998
Correspondence to: Irena Dawidson, Department of Cariology, Department
of Odontology, Karolinska Institutet, Box 4064, S-141 04 Huddinge, Sweden.
Tel: +46 8 728 8179, Fax: +46 746 7081, e-mail: Irena.Dawidson @ofa.ki.se
glands are controlled by both the sensory and autonomic
nervous systems. The parasympathetic system has the
main influence on the salivary secretion. 8-12Several studies have shown that the salivary flow rates can be
affected by neuropeptides.J3-18
It has also been shown that neuropeptides substance P
(SP) and vasoactive intestinal polypeptide (VIP) prevented the fall in the parotid gland weight after parasympathetic denervation and that VIP prevented the fall in
the sublingual gland weight induced by liquid diet.
These resuks suggest a trophic role for SP and VIP on
parotid gland and for VIP on sublingual gland, which can
also be exerted naturally as a resuk of their release from
nerve fibres containing these neuropeptides around the
acini. 19 The release of these neuropeptides in human
saliva has been investigated and the results of that study
showed that the concentration of the neuropeptides in
the saliva of healthy subjects varies with tile mode of
stimulation. 2° Furthermore, it was found that the release
of neuropeptides in the saliva of those healthy subjects
543
544
Dawidson et al
could be increased by acupuncture stimulation. 21 VIP,
one of the investigated neuropeptides found in the
parasympathetic nervous system, plays a crucial role.
Vasoactive intestinal polypeptide has been so called
due to its vasoactive properties. It is produced by both
CNS and PNS neurons, and neurons containing VIP have
been found in lymphoid organs and in free nerve endings in the skin, around blood vessels, hair follicles and
sweat glands. 22,23It has anti-inflammatory and immunoregulatory properties, 24,2sand influences salivary flow#6-34
The concentration of VIP in the saliva of xerostomic
patients who were treated with acupuncture was investigated in this study. We hypothesized that sensory stimulation through reflexes activates parasympathetic
efferents, increasing the release of VIP which apart from
stimulating salivary secretion, inhibits the inflammation
and has also a trophic influence on the gland tissue, thus
leading to an increase of the salivary flow rates in the
xerostomic patients.
Saliva collection
Paraffin-chewing stimulated saliva was collected from
the patients before the beginning of the study and then
after the acupuncture treatment was completed. The
standardized salivary flow test procedures used at the
department of Cariology were applied in this study? s The
patients were asked to refrain from eating, drinking and
smoking for at least 1 h prior to each experiment. Each
individual partAcipating in the study was tested at
approximately the same time of the day so as to consider
the differences in saliva production during the day. The
collected saliva was weighed in order to obtain precise
measurements (1 g was considered to respond to I mL).
The saliva samples were collected in small test tubes,
containing 1 mL 1 M acetic acid in order to neutralize the
enzymes that would otherwise destroy the neuropeptides. The samples were kept in ice during the experiment and were frozen to -70°C immediately after the
end of each session, awaiting the radio immunoassay
tests (RIA), that were to be carried out at a later date.
MATERIALS AND METHODS
Prior to the begining of the study, the ethical committee
at Huddinge Hospital, approved the experimental design.
The participants were informed about the study in writing and that they could withdraw at any moment.
Patients
Out of 65 patients that were treated with acupuncture for
xerostomia, 17 were chosen to participate in this study
due to their ability to produce enough stimulated saliva
for the radio immunoassay (RIA) analyses prior to the
start of the study. We were able to conduct RIA analyses
of VIP on the saliva of 10 of these patients, four men and
six women. Patient data are shown in Table 1.
Table I
The patients involved in this study
Patient/Gender
Age
Time of xerostomia
Aetiology
1. female
2. female
3. female
4. male
5. female
6. male
7. female
8. male
9. male
10. female
57
38
63
55
67
45
63
54
65
66
2 years
10 years
10 years
1.5 years
20 years
4 months
8 months
13 months
2.5 years
2 years
PSS
Unknown
PSS
Renal disease
SSS
Radiation treatment
Radiation treatment
Radiation treatment
Radiation treatment
Radiation treatment
PSS = Primary Sj6gren's Syndrome
SSS = Secondary Sj6gren's Syndrome
Neuropeptides (1998) 32(6), 543-548
Acupuncture treatment
An experienced acupuncturist carried out the acupuncture sessions, and the acupuncture procedure as well as
the points used for the treatment of xerostomia are also
described in detail in earlier studies, s-z The most frequently used points, used bilaterally and described in
Table 2 are St3, St6 in the face, Li4 in the hands and St36
and Sp6 in the legs) 6 The disposable needles used, were
Chinese and made of stainless steel, Hwato 0.32 x 40
mm, and Cloud & Dragon, 0.30 x 15, 30 and 40mm.
After standard sterilizing of the site, the needles were
inserted through the skin to the depth of 5 mm to 10
mm, and manipulated until the needle sensation (DeQi)
was obtained. DeQi is described as a feeling of heaviness
and ache, sometimes combined with the sensation of a
current originating from the point where the tip of the
needle is placed2 z When that sensation was achieved, the
needles were left in situ, and not manipulated again
unless a needle was displaced. All patients received a
double series of acupuncture treatments: 24 sessions of
20 min each.
Peptide analyses
VIP-like immunoreactivity (VIP-LI) was analysed in the
saliva samples collected from the subjects, using competitive radioimmunoassay (RIA).38 Vasoactive intestinal
polypeptide (VIP-LI) was analysed using antiserum VIP2
raised against conjugated natural porcine VIP. The antiserum does not react with gastrin, pancreatic polypeptide, glucagon, NPY or neurotensin. Intra- and interassay
© Harcourt Brace & Co. Ltd 1998
Sensory stimulation increases the release of vasoactive intestinal polypeptide
Table 2
545
The most commonly used acupuncture points
AP - POINT
LOCATION
TISSUES
SKIN
INNERVATION
MUSCLE
INNERVATION
St 3
Juliao
When the eyes look straight
forward, it is inferior to the
pupilla at the level of the lower
border of the alae nasi
m. levator labii
sup.
n. trigeminus,
r. ophtalmicus,
n. infraorbitale
n. facialis
St 6
Jiache
One finger width anterior and
superior to the angle of lower
jaw, at the prominence of the m.
masseter during mastication
m. masseter
n. trigeminus,
r. mandibularis
n. facialis,
r. mandibularis,
n. trigeminus
Li 4
Hegu
On the middle point of os
metacarpale li, on the
prominence of the 1st m. inter
ossei dorsales slightly towards
the side of the index.
m. interosseus
dors. m. abduct,
pollicis,
m. lumbricale I
n. radialis,
r. superficialis
(C 6, 7, 8)
n. ulnaris
(C 8, Th 1),
n. medianus
(C 8, Th 1)
St 36
Zusanli
10 cm below apex patellae, one
finger width lateral to the crista
anterior tibiae
m. tibialis ant.
n. cutaneus lat.
(L 5, S 1,2)
n. peroneus
Sp 6
Sanyinjiao
10 cm above the highest point
of the malleolus medialis at the
posterior border of the tibia
m. flexor
digitorium long.
m. tibialis post.
n. sapheneus
(L 3,4)
n. tibialis
(L 4, S 2, 3)
coefficients of variation were 9% and 13%, respectively?9
The lower detection limit in all saliva samples was 0.1
fmol/mL for all peptide assessments. 4°
High-performance liquid chromatography (HPLC):
reverse-phase HPLC was applied to samples extracted
with 2 M acetic acid in 4% EDTA. HPLC was perfomed
using a Waters Delta Pac C18 300 _h, 3.9 mm × 15 cm column, eluted with 40-min linear gradient of acetonitfile in
water containing 0.1% trifluoracetic acid. Two Pharmacia
P3500 pumps were controlled by Pharmacia GP250 gradient programmer. A gradient of 20-50% acetonitrile was
used. Samples were passed through Mfllipore GS filters
(0.45 ~m) prior to chromatography to remove particulate
matter. Samples of 200 ~tL were injected into columns.
l~ractions of 0.5 mL were collected at an elution rate of
1.0 mL/min. Each fraction was lyophilized and redissolved in 100 ~tL distilled water before analysis. The fractions were assayed for immunoreactivity in the tubes
used for their collection? s
Statistical a n a l y s e s
Wilcoxon's test (paired two samples) was used in order to
compare the concentrations of VIP in the saliva before
the beginning of the study and after the acupuncture
treatment was completed. A probability value of p < 0.05
was considered significant.
RESULTS
Acupuncture treatment resulted in an increase of saliva
production. The concentrations of VIP in the saliva were
© Harcourt Brace & Co. Ltd 1998
pmol/L
50
"
40
)
mm
.
•
30
25
20
15
10
5
0
1
2
3
4
5
6
7
OBefore AP mAftor AP
8
9
10
Patients
Fig. 1 The concentration of VIP in the saliva of xerostomic
patients before and after acupuncture treatment (AP).
significantly higher after the end of acupuncture treatment as compared to the base line levels (before the
AP was started). The results are visualized in Figure 1
(p < 0.05). The correlation between the changes in VIPconcentration and salivary flow was 0.66.
HPLC showed a distinct immunoreactive component
with regard to VIP, as refected by a main peak eluting in
the position of the corresponding synthetic peptide. No
evidence was found to indicate presence of multiple
immunoreactive components (Fig. 2).
DISCUSSION
The xerostomic patients that were treated with acupuncture showed an increase in salivary secretion rates? -z,41
We found a significant increase of the concentration of
VIP in the stimulated saliva of the 10 patients that were
Neuropeptides (1998) 32(6), 543-548
546
Dawidson et al
100
90,
80,
70,
60,
50,
~'
D.
40'
30,
20'
10'
I---
I
-'
m
I
J
,,.,,,.,.ono,,,H ......•...............,,,,,,n,noo,,,,,. ......°.......,,o.oo.,
5
9
13 17 21 2 5 2 9 33 37 41 4 5 ~
5 3 57 61 65 6 9 73 77 81 8 5
Fraction number
Fig. 2 Reverse-phase HPLC of vasoactive intestinal polypeptide
immunoreactivity (VIP-LI) in extracts from human saliva. The
elution profile of VIP is indicated by an arrow. The VIP-LI had its
mark peak eluting in the position of the corresponding synthetic
peptide.
investigated in this study and it was correlated to the
increase of the salivary secretion.
The secretion of saliva is regulated by the autonomic
nervous system. It is influenced by the excitation of afferent nerve fibres from the masticatory system leading to
reflex excitation of salivary parasympathetic and sympathetic activity. It has been shown that salivary neurons in
the lateral reticular formation of the lower brain stem
react to stimulation of afferent branches of the trigeminal. Input from group II and group III afferent fibres of
the trigeminal nerve activate salivary efferent neurons,
resulting in salivary secretion. 42
The connection between VIP and salivary functions
has been investigated in several studies. VIP-containing
nerves have been found in close association with the
acini, ducts and blood vessels,/5,~6 as well as in close proximity of mucous endpieces and palatal glands, intercalated ducts of the parotid gland and excretory ducts of
parotid, labial and palatal glandsY,~8Animal studies have
shown that VIP can influence the saliva secretion, producing relatively small amounts of saliva, the most from
gland, submandibularis, the least from gland, sublingualis, and that VIP can increase the release of proteins.
Like SP and calcitonin gene-related peptide (CGRP), VIP
increases significantly the blood flow in the salivary
glands. Together with CGRP, VIP also enhances the
salivary secretion evoked by SP and acetylcholille. 12,13,26-34,43,44 It has also been demonstrated that
repeated infusions of SP and VIP are capable of preventing the expected reduction in gland weight following
denervation or liquid diet29 Human studies have shown
that VIP alongside SP is a potent vasodilator in the
human submandibular gland/4 and it has been shown
Neuropeptides (1998) 32(6), 543-548
that VIP potentiates the salivary response to acetylcholine. 29 The finding of neuronal VIP in the salivary
glands, its release upon nerve stimulation, and its known
effect on local blood flow support the view that VIP is
neurotransmitter in the salivary glands. 2~,26
Apart from the secretory and vasculomotor influence
of VII', it has been suggested that this neuropeptide can
also function as a growth factor in wound healing and
angiogenesis, and that it has atrophic influence on the
salivary gland tissue. 24,45There are also suggestions that
immune cells as well as nerve cells can synthesize VIP/6
and that there are specific receptors; VIP-R1 and VIP-R2
on human T-cell that bind VIP.47,48 The immunoregulatory effect of VIP's immune response seems to be the
inhibition of lymphocyte migration by way of modulating their adherence to the vascular endothelium. 49 VIP
exerts its anti-inflammatory effect by downregulating the
immune response when the inflammation has acted out
its role. 2~
Several previous and ongoing investigations have
shown that acupuncture can improve the salivary secretion of xerostomic patients and that the increased salivary flow rates persist during a long observation
period? -z,41 It is of utmost importance, however, to elucidate the mechanisms behind the effect of acupuncture
on salivary gland function in order to achieve a scientifically acceptable explanation of the efficacy of this treatment. Otherwise there are only a few ways of alleviating
xerostomia, none of them very effective or capable of
producing any long-lasting results? °-53
Acupuncture has been used in China for treatment of
diseases and their symptoms for more than 5000 years.
The vast empiric knowledge that has been accumulated
during the ages has propelled this method of treatment
into the western medical world, and although it is still
regarded with healthy scepticism, acupuncture is widely
used. Many scientific studies have been conducted during the recent decades in order to elucidate the mechanisms behind the effects of acupuncture, as traditional
Chinese philosophy is unacceptable to the western scientific community. The results of these numerous studies
have led to a better understanding of the function of sensory stimulation as well as to an acceptance of acupuncture as a therapeutic method in the treatment of different
illnesses and acute pains. As more clinical investigations
limit or broaden the field of the use of acupuncture, its
mechanisms, when found effective, must be investigated
in each instance, in order to provide a scientific basis for
its application.
The investigations of acupuncture mechanisms have
revealed that acupuncture stimulation leads to a release
of endogenous opioids and oxytocin. The endorphins,
especially [~-endorphin, bind to opioid receptors, affecting blood pressure and body temperature as well as
© Harcourt Brace & Co. Ltd 1998
Sensory stimulation increases the release of vasoactive intestinal polypeptide
exerting p a i n control b y their affinity to g-receptors, s4
The pain sensitivity a n d a u t o n o m i c f u n c t i o n s are influe n c e d o n the central level, t h r o u g h the h y p o t h a l a m u s ,
m i d b r a i n a n d b r a i n s t e m nuclei, s4 It has b e e n suggested
that VIP-release d u e to sensory s t i m u l a t i o n was the
a g e n t responsible for t h e effect of a c u p u n c t u r e - l i k e stimuli that caused a n increase of t e m p e r a t u r e a n d microcirculation i n the skin. ss,s6 The i n f l u e n c e of a c u p u n c t u r e o n
salivary secretion m i g h t be m e d i a t e d via the p a r a s y m p a thetic n e r v o u s system as reflexive response to sensory
s t i m u l a t i o n of g r o u p III afferent A-delta nerve fibres a n d
possibly C-fibres of n. trigeminus, leading to activation of
the salivary n e u r o n s i n the lateral reticular formation of
the lower b r a i n stem.
We c o n c l u d e d that one of the m e c h a n i s m s t h r o u g h
which the a c u p u n c t u r e s t i m u l a t i o n can lead to a n
increase of the salivary flow rates i n xerostomic patients
m i g h t be the release of VIP. The a n t i - i n f l a m m a t o r y
properties of VIE together with its role as growth factor
could, aside from its secretory influence, provide a n
e x p l a n a t i o n of the l o n g - t e r m positive effects of a c u p u n c ture treatment.
The Swedish Dental Society, the Swedish Patent R e v e n u e
Research Fund, the Gustav Vth 80-year A n n i v e r s a r y
F o u n d a t i o n , the Professor N a n n a Schvartz F o u n d a t i o n
a n d the Swedish Society against R h e u m a t i s m (RMR)
supported this study.
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