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Electroacupuncture Treatment Improves Learning-Memory Ability and Brain Glucose Metabolism in a Mouse Model of Alzheimer’s Disease: Using Morris Water Maze and Micro-PET


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Introduction. Alzheimer's disease (AD) causes progressive hippocampus dysfunctions leading to the impairment of learning and memory ability and low level of uptake rate of glucose in hippocampus. What is more, there is no effective treatment for AD. In this study, we evaluated the beneficial and protective effects of electroacupuncture in senescence-accelerated mouse prone 8 (SAMP8). Method. In the electroacupuncture paradigm, electroacupuncture treatment was performed once a day for 15 days on 7.5-month-old SAMP8 male mice. In the normal control paradigm and AD control group, 7.5-month-old SAMR1 male mice and SAMP8 male mice were grabbed and bandaged while electroacupuncture group therapy, in order to ensure the same treatment conditions, once a day, 15 days. Results. From the Morris water maze (MWM) test, we found that the treatment of electroacupuncture can improve the spatial learning and memory ability of SAMP8 mouse, and from the micro-PET test, we proved that after the electroacupuncture treatment the level of uptake rate of glucose in hippocampus was higher than normal control group. Conclusion. These results suggest that the treatment of electroacupuncture may provide a viable treatment option for AD.
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Research Article
Electroacupuncture Treatment Improves Learning-Memory
Ability and Brain Glucose Metabolism in a Mouse Model of
Alzheimer’s Disease: Using Morris Water Maze and Micro-PET
Jing Jiang,1Kai Gao,2Yuan Zhou,1Anping Xu,1Suhua Shi,1Gang Liu,3and Zhigang Li1
1Beijing University of Traditional Chinese Medicine, Beijing 100029, China
2Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center,
Peking Union Medical College, Beijing 100021, China
3Community Health Service Center of Dongcheng District, Beijing 100010, China
Correspondence should be addressed to Zhigang Li; lizhigang@.com
Received  December ; Revised  January ; Accepted  January 
Academic Editor: Mani Vasudevan
Copyright ©  Jing Jiang et al. is is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction. Alzheimer’s disease (AD) causes progressive hippocampus dysfunctions leading to the impairment of learning and
memory ability and low level of uptake rate of glucose in hippocampus. What is more, there is no eective treatment for AD. In this
study, we evaluated the benecial and protective eects of electroacupuncture in senescence-accelerated mouse prone  (SAMP).
Method. In the electroacupuncture paradigm, electroacupuncture treatment was performed once a day for  days on .-month-old
SAMP male mice. In the normal control paradigm and AD control group, .-month-old SAMR male mice and SAMP male
mice were grabbed and bandaged while electroacupuncture group therapy, in order to ensure the same treatment conditions, once a
day,  days. Results. From the Morris water maze (MWM) test, we found that the treatment of electroacupuncture can improve the
spatial learning and memory ability of SAMP mouse, and from the micro-PET test, we proved that aer the electroacupuncture
treatment the level of uptake rate of glucose in hippocampus was higher than normal control group. Conclusion. ese results
suggest that the treatment of electroacupuncture may provide a viable treatment option for AD.
1. Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative
disease, which is the most widespread cause of dementia
and its incidence will continue to increase rapidly as the
population ages []. It is characterized by the progressive
decline of memory and cognitive function and changes in
behavior and personality []. Despite the fact that extensive
research is focused on AD, there is no eective treatment for
this disease []. erefore, the therapeutic of AD is urgent to
be proposed.
Electroacupuncture (EA) treatment is a type of needling
therapy from Journal of Acupuncture and Moxibustion,num-
ber ,, which combines needling with electric stimula-
tion, connecting needles of the point group concerned (
points make up a group) with pulse current from the electric
stimulator []. ere is a dual-directional pulse current
(intermittent oscillatory current), sin wave, square wave,
and so forth, with characteristics such as continuous wave,
sparse-dense wave, intermittent wave, undulate wave, and
saw tooth wave. e frequency most commonly used is –
 times/sec. over  times/sec. which is used less. What
is more, the proper intensity of the stimulation is marked by
a muscular twitch around the acupoint and a comfortable
sensation []. EA treatment has advantages like many kinds
of oscillation waves, wide range of frequency, and stable
function [].
So far, EA treatment has yielded neuroprotective function
in animal models of depression, spinal cord injury [,],
cerebral ischemia-reperfusion injury [], stork [,,,
], and many kinds of pain []. Clinically, EA treatment
has been shown to have ecacy in curing many kinds of
neurological disease, such as depression [,], spinal cord
injury [], cerebral ischemia-reperfusion injury [],
stork [], and many kinds of pain []. us, some
of researcher proposed that since the EA treatment could
Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2015, Article ID 142129, 7 pages
Evidence-Based Complementary and Alternative Medicine
protect the central nervous system it may be used as an
alternative treatment for AD []. However, more research is
needed to prove this conclusion.
e aim of this study was to assess the ecacy of EA
treatment in curing AD. We utilized the mouse model of
AD, senescence-accelerated mouse prone  (SAMP), which
develops the learning and memory impairment and the mood
disorder. Here, we present the ethology and in vivo imaging
evidence that EA treatment over a period of half a month
improves the learning and memory ability and brain glucose
metabolism in AD, specically in the hippocampus of the
SAMP mouse. is nding extends our previous EA work in
the models of the central nervous injury to demonstrate that
EA treatment is also eective in protecting the brain against
2. Method and Materials
2.1. Animals. Senescence-accelerated mouse prone 
(SAMP) and the cognate normal senescence-accelerated
mouse-R (SAMR) breeding pairs were kindly provided
by Professor Takeda at Kyoto University, Japan []. e
animals were housed in a barrier facility of the Experimental
Animal Centre of First Teaching Hospital of Beijing University
of Traditional Chinese Medicine and under live conditions
of controlled temperature ( ±C), a  h/ h dark/light
cycle, and sterile drinking water and standard pellet diet
ad libitum. All experiments were performed according to
the National Institute of Health Guide for the Care and Use
of Laboratory Animals (NIH publications number -).
irty .-month-old SAMP male mice were divided into
two groups (𝑛=10per group): SAMR normal control (Rc)
group, SAMP Alzheimer’s disease control (ADc) group, and
SAMP electroacupuncture (EA) group.
2.2. Acupuncture Manipulation. In the EA group, elec-
troacupuncture treatment was performed once a day for 
days (no treatment on the eight day). e prescription of
acupuncture points included DU Baihui,DUShuigou,
and EX-HN Yintang (the signicant extra point). e
locations of these points were according to the National
Acupuncture Society for Experimental Research developed
the “laboratory animal acupuncture atlas. Huatuo card ,
. inch needle was used for treatment. Pricking method was
DU Baihui and EX-HN Yintang. Needle depth was . cm
and taped. e needle handle was connected with HANS-
LH electroacupuncture device (Peking University Institute
of Science Nerve and Beijing Hua Wei Industrial Development
Company), sparse wave,  Hz of the frequency,  V of the
voltage, and . mA of the current intensity.
In the Rc group and ADc group, do not do any treatment
under the same rearing conditions, while grabbing and
bondage the mice in order to ensure the same treatment
conditions, once a day,  days.
2.3. Morris Water Maze Behavioral Test. e Morris water
maze consisted of a circular tank ( cm in diameter,  cm in
height) lled with water to a depth of  cm maintained at 
±C and rendered opaque with blue-black ink. A removable
circular platform (. cm diameter,  cm height) with its top
surface  cm below the water was located inside the pool. e
area of the pool was conceptually divided into four quadrants
(NE, NW, SW, and SE) of equal size. Data were collected by
a video camera (TOTA-d,Japan)whichwasxedtothe
ceiling of the room and connected to a video recorder and an
automated tracking system (China Daheng Group, Beijing,
In this behavioral test, mice are placed in the pool of water
containing a platform just below the surface of the water. ey
escape from the maze when they nd the platform. Distal
visual cues are arrayed around the room, and in general, mice
are able to learn the location of the hidden platform based on
these cues.
2.4. Hidden Platform (Place) Testing. is portion of the test
assesses the ability of the mice to nd the platform under
conditions where they cannot directly see it but must either
remember it is relative to external cues or perform a search
for it. e platform was placed cm under the surface of the
water, and the water was opaque by a suspension of dark
blue, nontoxic tempera paint. e platform was placed in
a dierent location from that used in the visible platform
testing. Each mouse was released from one of  locations and
had  s to search for the hidden platform. At the end of each
on the platform for  s. Prominent spatial cues were arrayed
around the room. e investigator is also a powerful spatial
releasing the mouse. Eight trails per day for  consecutive
days were performed with the location of the platform kept
constant. We recorded the time that the mouse found the
platform needed, and we call it escape latency.
2.5. Probe Trail. e day aer the completion of hidden
was placed in the pool once for  s, starting from the same
starting location as was used rst in hidden platform testing.
e time spent swimming in the quadrant where the platform
had been was recorded. is is considered to be the most
specic test for spatial memory. We recorded the time that
percentage of total time spent in swimming to the platform
2.6. Micropositron Emission Tomography. Before experi-
ments, each mouse (. months,  g) for blood glucose
monitoring, the results showed the normal range (.
. mmol/L) could be used for micro-PET detective (18F-
FDG PET tracer was provided by the Chinese Medicine
Research Institute PET Room; PET imaging system using
Siemens INVEON PET/CT imaging system). Six hours of
water deprivation before the experiment. e mice were
placed in the suction chamber, inhaling the oxygen mixed
thesia, approximately .. MBq 18F-FDG PET tracers
Evidence-Based Complementary and Alternative Medicine
were injected via vena of tail. Aer the 18F-FDG PET tracer
uptake for  min, the mice were placed on the scan bed in
prone position, the mice and scanner long axis were parallel,
eld of view. en the micropositron emission tomography
began to collect the image. During this progress, the mice
were anesthetized by the oxygen mixed with .% isourane
( L/min).
2.7. Micropositron Emission Tomography Image Reconstruc-
tion. Filtered back projection (FBP) and CT photon attenua-
tion correction were used for image reconstruction. Dynamic
micro-PET image frames are taken  s/frames.
2.8. Region of Interest Selection. e three-dimensional
region of interest te chnology was applied for manual selection
of the hippocampus three-dimensional region of interest in
transverse, coronal, and sagittal planes. en calculate the
uptake rate of per gram with the region of interest.
2.9. Statistical Method. AlldatawereanalyzedbySPSS(ver-
sion .; SPSS, Inc., Chicago, IL, USA). All measurements
were performed by an independent investigator blinded to
the experimental conditions. e results in the gures are
expressed as the mean ±standard deviation. Dierences
within or between normal distributed data were analyzed by
analysis of variance (ANOVA) followed by Huynh-Feldt test
(for Morris water maze test). Statistical signicance was set at
𝑃 < 0.05.
3. Results
3.1. Eect of Electroacupuncture in Spatial Learning Ability
of SAMP8 Mouse in the Morris Water Maze Test. e eect
of electroacupuncture in spatial location ability of SAMP
mouseintheWMWtestiselucidatedinFigure (a).Wecan
see that with the training time extension, the escape latency
of all groups had shown a downward trend (Figure (b)). e
AD control group showed marked retardation in the escape
latency, probably due to the memory decits resulting from
the rapid aging process impairment of learning and memory.
e analysis of the escape latency revealed that the mouse
in EA group had signicantly reduced the escape latency
compared with the AD control group (𝑃 < 0.05,Figure (c)).
3.2. Eect of Electroacupuncture in Spatial Memory Ability of
SAMP8 Mouse in the Morris Water Maze Test. To investigate
the eect on spatial memory ability, the performance in
percentages of time spent swimming to the expected position
of the platform. A higher percentage of time spent in the
platform quadrant is interpreted as a higher level of memory
retention []. In this probe trial, we found that compared
with AD control group, EA group spent higher time in the
platform quadrant (𝑃 < 0.01). What is more, in percentage of
time spent in the platform quadrant, EA group and normal
group had no signicant dierence in statistics (𝑃 = 0.223,
Figure ).
3.3. PET Imaging of Mice Hippocampus. Because of the eects
of the tail vein injection, condition of anesthesia, and the
metabolism of the 18F-FDG, four animals of each group could
successfully guarantee the completion of micro-PET test.
Use the same color standard and color code from top
high to the bottom low to display the metabolic rate of the
glucose. e le of the observer is the right of the animal.
18F-FDG of hippocampus is higher than Alzheimer’s disease
group (Figure ).
3.4. 18F-FDGUptakeRateofperGraminHippocampusTissue.
To study that the treatment of electroacupuncture corre-
sponds to enhancing the glucose metabolic activity in hip-
pocampus, 18F-FDGPETscanwasperformedonthemice.
e result showed that aer treatment of electroacupuncture
theuptakerateof18F-FDG in hippocampus was higher
than Alzheimer’s disease group and normal control group
(Figure ).
4. Discussion
In the current research, we studied the eect of elec-
troacupuncture on animal model of Alzheimer’s disease using
whether the treatment of electroacupuncture can improve
the condition of Alzheimer’s disease. Using the Morris water
the spatial learning and memory ability of the SAMP mouse
had improved. Further, the result of micro-PET revealed that
treatment of electroacupuncture can increase the uptake rate
from animal behavior and in vivo imaging lead us to conclude
that the treatment of electroacupuncture may play a curable
role in Alzheimer’s disease, particularly in the learning and
memory ability.
4.1. Alzheimer’s Disease in Traditional Chinese Medicine and
the Acupuncture Prescription. Alzheimer’s disease belonged
to encephalopathy in Chinese medicine. It is caused by de-
ciency of jing and blood, with the aged condition, leading to
serious brain function disorder. It is characterized by forgetful
and personality changes []. In the treating principle of
Chinese medicine, according to the principle “the brain is
the house of mentality,” “the Governor Vessel ... entering
the brain and extending up to the very top of the head,
based on the close relationship brain-mentality and brain-
Governor Vessel, we proposed “dredging the Governor Vessel
In the selection of acupoints, we chose DU Baihui,DU
 Shuigou, and EX-HN Yintang as the main points. DU
Baihui, a meridian point of the Governor Vessel, and the
meeting point of Governor Vessel, the three Yang Meridians
and Moxibustion (zhen jiu jia yi jing ), also named Sanyang-
wuhui,Dianshang,Wu hui.Itislocatedonthehead,cun
directly above the midpoint of the anterior hairline. Its
indication is headache, dizziness, palpitation due to fright,
Evidence-Based Complementary and Alternative Medicine
Group Day 1 Day 2 Day 3 Day 4 Day 5
Normal control group
Alzheimer’s disease
control group
41.85 ± 6.32 32.88 ± 8.78 27.98 ± 10.92 24.82 ± 6.64 19.21 ± 12.63
57.21 ± 3.68 57.26 ± 5.09 54.70 ± 7.57 53.16 ± 8.16 53.67 ± 8.28
57.65 ± 4.15 51.25 ± 9.08 49.42 ± 14.01 48.32 ± 10.25 47.10 ± 10.78
Escape latency (s)
Day 1Day 2Day 3Day 4Day 5
Normal control group
Alzheimer’s disease group
Electroacupuncture group
P < 0.05
control group
disease group
Escape latency (s)
F : (a) Comparison of the escape latency of all groups. (b) e trend of the escape latency of all groups. (c) Comparison the mean of
the escape latency of all groups.
control group
disease group
e time spent in
platform quadrant (%)
P < 0.01
control group
disease group
e time spent in
platform quadrant (%)
F : (a) e percentage of time spent in platform quadrant of each group. (b) e percentage of time spent in platform quadrant of each
amnesia, corpse-like syncope, aphasia from apoplexy, manic-
depressive psychosis, epilepsy, hysteria, and so forth. DU 
Shuigou is a point on the Governor Vessel, Hand-Yangming,
and Foot-Yangming, also called Renzhong. Its location is on
the philtrum. It is used for coma, syncope, manic-depressive
so forth. EX-HN Yintang, an extra point, is seen in Bian
Que’s Jade Dragon Classics of Acupuncture and Moxibustion
(Bian Que Shenying Zhenjiu Yulong Jing). It is on the forehead,
at the midpoint between the eyebrows. Headache, vertigo,
insomnia, and puerperal faintness are the indication of EX-
acupuncture prescription.
4.2. Senescence-Accelerated Mouse-P8 (SAMP8) Is an Optional
Animal Model for Alzheimer’s Disease. e senescence-
accelerated mouse (SAMP) is a spontaneous animal model
of Alzheimer’s disease, and it develops early memory distur-
bances and changes in the blood-brain barrier resulting in
decreased eux of amyloid-beta protein from the brain [].
is nontransgenic animal model with great utility can be
better simulated for the memory decits and the low level
uptakerateofglucoseinhippocampus[]. So, in the current
research, this kind of animal model can help us to nd the
eect of electroacupuncture treatment in curing Alzheimer’s
4.3. Eect of Electroacupuncture in Morris Water Maze. e
Morris water maze (MWM) is one of the most common tasks
Evidence-Based Complementary and Alternative Medicine
F : Right side hippocampus of the mice in micro-PET scan image. (a) Normal control group; (b) Alzheimer’s disease group; (c)
electroacupuncture treatment group. Color code: min = , max = .
ID/g (%)
control group
disease group
P < 0.01
control group
disease group
ID/g (%)
F:(a)euptakerateof18F-FDG per gram in hippocampus. (b) e uptake rate of 18F-FDG per gram in hippocampus.
used to assess spatial learning and memory ability in rodents
[]. Spatial navigation performance in the hidden goal task
(HGT), a real-space human analogue of the Morris water
maze, can identify mild cognitive impairment (MCI) patient
with memory impairment of the hippocampus type, a known
indicator of incipient Alzheimer’s disease []. In our study,
we found that aer the treatment of electroacupuncture, the
spatial learning and memory ability of the SAMP mouse had
improved compared with the nontreatment SAMP mouse,
which suggested that the electroacupuncture may improve
the cognitive ability of Alzheimer’s disease patients.
4.4. Eect of Electroacupuncture in Micro-PET. Studies sug-
gested that the cognitive impairment of Alzheimer’s disease
to a certain extent results from the low level of uptake rate
of glucose in hippocampus []. So in our current study, we
used the micro-PET to get the in vivo image of the uptake rate
of glucose in hippocampus.
Positron emission tomography is a noninvasive func-
which makes the use of radioactive marker to analyze the
metabolism condition in the brain, images the distribution of
biologically targeted radiotracer with high sensitivity []. It
can directly reect the activity of neurons, which becomes an
important tool for diagnosing disease and evaluating ecacy
[]. With the growing importance of animal research in
modern molecular biology, the appearance of micropositron
emission tomography (micro-PET) makes the possible of
in vivo molecular imaging. Development of micro-PET
instrumentation for small animal imaging and the availability
of positron-emitting tracers have made this technology acces-
sible for the noninvasive, quantitative, and repetitive imaging
of biological function in living animals. e development
of new probes and positron-imaging based reporter genes
has extended micro-PET applications to investigations of
metabolism, enzyme activity, receptor-ligand interactions,
protein-protein interactions, gene expression, adoptive cell
therapy, and somatic gene therapy [].
In this research, the 18F-FDG uptake condition in the
hippocampus of mice was imaged by micro-PET, which can
Evidence-Based Complementary and Alternative Medicine
show the metabolism level in the hippocampus of Alzheimers
disease mice. Seeing from the images, the 18F-FDG uptake
condition of electroacupuncture treatment group is higher
than Alzheimers disease group. With further calculation and
comparison of the 18F-FDG uptake rate of each group, we can
see that the electroacupuncture treatment group is the high-
est, normal control group is in the middle, and Alzheimer’s
electroacupuncture treatment the glucose metabolism level
in the hippocampus of the Alzheimer’s disease animal model
would be higher. erefore, we could draw the conclusion
that the treatment of electroacupuncture could improve the
level of uptake rate of glucose in hippocampus in Alzheimer’s
disease animal.
5. Conclusion
In this research, using the test of Morris water maze and
the micro-PET in Alzheimer’s disease animal model SAMP
mouse, we found that the treatment of electroacupuncture
can improve the spatial learning and memory ability by
heightening the level of uptake rate of glucose in hippocam-
pus. is is an interesting notion; however, further research
is needed to prove.
Conflict of Interests
e authers declare that there is no conict of interests
regarding the publication of this paper.
is research was supported by National Natural Science
Foundation of China (no. ).
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... However, electric stimulation was not applied at these acupoints. In animal studies, EA stimulation was applied on the head and neck region or KI3 on the ankle region [69][70][71][72]. Further studies are required to test the potential effect of electric stimulation on acupoints located in the head and neck region for improving cognitive decline. ...
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Although Electroacupuncture (EA) has been reported to be potentially effective for cognitive disorders, there is limited information about which domains of cognitive function can be improved by EA treatment. Sixty patients with MCI were randomly assigned (1:1:1) to groups to receive 24 sessions over 12 weeks of EA, sham EA, or usual care. In the EA group, electric stimulation was applied at bilateral PC6 and HT7. Various cognitive tests included in the Seoul Neuropsychological Screening Battery II (SNSB-II) were performed at baseline and post-treatment to explore effects of EA on five cognitive domains: attention, language, visuospatial function, memory, and frontal/executive function. Among 60 randomized participants (63.7 ± 7.1 years, 89.7% females), 45 (75%) completed the study. Of the five cognitive function domains of SNSB-II, the T score of visuospatial function showed a tendency to be higher in the EA group than in the usual care group at post-treatment assessment (mean difference: 10.16 (95% CI, 1.14, 19.18), Cohen’s d = 0.72, p = 0.0283). According to the results of this pilot study, the estimated effect size of EA on the visuospatial function of MCI patients compared to usual care was medium. Large-scale clinical trials are needed to confirm effects of EA on cognitive functions.
... Furthermore, EA stimulation at GV 20 and GV 24 acupoints could effectively ameliorate the cognitive deficits of PS cDKO mice (Figure 1). Consistent with our result, previous study proved that EA treatment could improve learningmemory ability of the AD mice model and ameliorate poststroke cognitive impairments via inhibition periinfarct astroglia and microglial/macrophage P2 purinoceptors-mediated neuroinflammation [34][35][36]. In addition, PS cDKO mice exhibited obvious deficits in LTP induction at SC-CA1 synapses, and impaired magnitude of LTP in PS cDKO mice was ameliorated by EA treatment (Figure 2). ...
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Neuroinflammation is considered as one of the crucial pathogenesis in promoting neurodegenerative progress of Alzheimer’s disease (AD). As complementary and alternative therapy, electroacupuncture (EA) stimulation has been widely used in clinical practice for anti-inflammation. However, whether EA promotes the cognitive deficits resulting from neuroinflammation in AD remains unclear. In this study, the presenilin 1 and 2 conditional double knockout (PS cDKO) mice, exhibited a series of AD-like pathology, robust neuroinflammatory responses, and memory deficits, were used to evaluate the potential neuroprotective effect of EA at Baihui (GV 20) and Shenting (GV 24) by behavioral testing, electrophysiology recording, and molecular biology analyzing. First, we observed that EA improved memory deficits and impaired synaptic plasticity. Moreover, EA possesses an ability to suppress the hyperphosphorylated tau and robust elevated NLRP3, ASC, Caspase-1, IL-1β, and IL-18 in PS cDKO mice. Importantly, MCC950, a potent and selective inhibitor of NLPR3 inflammasome, has similar effects on inhibiting the hyperphosphorylated tau and the robust elevated NLRP3 components and neuroinflammatory responses of PS cDKO mice as well as EA treatment. Furthermore, EA treatment is not able to further improve the AD-like phenotypes of PS cDKO mice in combination with the MCC950 administration. Therefore, EA stimulation at GV 20 and GV 24 acupoints may be a potential alternative therapy for deterring cognitive deficits in AD through suppression of NLRP3 inflammasome activation.
... Each mouse in the EA group was immobilized in a bag during EA treatment. Three acupoints were selected based on our previous findings: 27,29,30 Yintang (GV 29), Baihui (GV 20) and Shuigou (GV 26). The GV 29 and GV 20 acupoints were transversely punctured to a depth of 2e3 mm using 0.25 mm  13 mm disposable sterile acupuncture needles (Beijing Zhongyan Taihe Yiliao Qixie Youxian Gongsi; Beijing, China). ...
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Objective To determine whether electro-acupuncture (EA) therapy could improve the cognitive functions of amyloid precursor protein Swedish mutation (APPswe)/presenilin 1 deleted in exon 9 (PS1dE9) mice and examine whether EA treatment could attenuate neuroinflammation by targeting the toll-like receptor 4 (TLR4)/myeloid differentiation primary response factor 88 (MyD88) signaling pathway. Methods Twenty-seven double transgenic APPswe/PS1dE9 mice were randomly allocated into three groups: an Alzheimer's disease model group (AD group), a medication group (M group) and an EA treatment group (EA group). Each group contained nine mice, and nine wild-type mice were used in a normal group (N group). The animals in the M group were treated with oral administrations of 0.92 mg/kg donepezil hydrochloride for 15 days. For animals in the EA group, EA treatments were used on the Yintang (GV 29) and Baihui (GV 20) acupoints for 20 minutes, and the Shuigou (GV 26) acupoint was pricked without needle retention following EA treatments. Following treatments, the spatial learning and memory of the mice were measured using the Morris water maze test. The expression levels of TLR4, MyD88, nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) were analyzed by immunohistochemical staining and western blot. Results The escape latencies of the M and EA groups were significantly lower than those of the AD group (vs M, P = .002; vs EA, P < .001). Moreover, compared with the AD group, the numbers of platform crossings was higher (vs M, P = .038; vs EA, P = .008) and the latency time for target quadrants was longer (vs M, P = .002; vs EA, P = .001) in the M and EA groups (P < .05). Furthermore, in the M and EA groups, the expression levels of TLR4, MyD88, NF-κB and iNOS decreased significantly compared with those of the AD group (all P < .01). Conclusion EA treatment enhanced the memory and learning abilities of APPswe/PS1dE9 mice by regulating the TLR4/MyD88 inflammatory signaling pathway.
... In this study, it was demonstrated that electroacupuncture may improve spatial learning and memory abilities and be neuroprotective in the hippocampus. These results were consistent with our previous research [31,32]. Although the escape time of the EA group mice during the hidden platform trial in the Morris water maze on the fourth day was significantly higher than that on the day before, they performed the best among the three experimental SAMP8 mouse groups on the fifth day. ...
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Alzheimer's disease (AD) is one of the most serious public health concerns facing the world. Its characteristic feature is neuroinflammation due to microglial activation. Electroacupuncture is one of the therapies employed to improve the condition of patients with AD, although its mechanism of action is still to be determined. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor that is involved in regulating neuroinflammation in AD. In this study, we applied senescence-accelerated mouse-prone 8 mice as the AD animal model, used the Morris water maze, and applied hematoxylin and eosin staining, immunofluorescence double staining, and Western blotting, to explore the effects and potential mechanisms of action of electroacupuncture. In summary, this study suggested that electroacupuncture treatment could improve the learning and memory abilities (p<0.05) and protect neurons. These effects result from acupuncture could upregulate TREM2 expression in the hippocampus (p<0.01), which was essential for the anti-inflammatory effects in the AD animal model. However, further studies are needed to conclusively demonstrate the mechanism of action of electroacupuncture in AD.
... (17) EA Regulates Metabolism EA Regulates Glucose Metabolism The brain relies almost exclusively on glucose as its source of energy. Reduced cerebral glucose metabolism may be an important trigger for the onset of AD. (54) EA can increase the glucose uptake rate in the hippocampus (18,19) and temporal regions. (20) Adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (AKT) serine/ threonine kinase are 2 important metabolic homeostatic factors for glucose metabolism. ...
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Alzheimer’s disease (AD) is the main type of dementia affecting elderly people. The medicines used for treating AD have limits in their ability to alleviate cognitive and functional decline. Electroacupuncture (EA), an economical alternative and complementary therapeutic measure used in Chinese medicine, has strong clinical applicability, and its treatment effects are more reliable as its stimulation factors can be standardized. EA has been effectively used for ameliorating spatial learning and memory impairment in AD patients and rodent AD models. Here, we summarized the mechanisms of EA on rodent AD models, aiming to provide a theoretical basis for identifying new targets and research directions, and exploring appropriate EA stimulation parameters, then provide a detailed methodology to optimize the effects of EA, ultimately reducing the heavy burden of treating AD patients on families and countries. Our review showed that 8 acupoints were used when treating AD animals; Baihui (GV 20) was the most frequently used. Four mechanisms of EA were studied: (1) protection of cerebral neurons from oxidative stress, apoptosis, neuroinflammation, synaptic plasticity and hormone levels; (2) regulation of metabolism, including glucose metabolism and plasma metabolism; (3) regulation of brain-derived neurotrophic factor; and (4) regulation of β-amyloid peptide protein deposition.
... Studies have also shown that the effect of acupuncture on the brain is integrated at multiple levels, and EA is progressively being used in more clinical practices (Sun et al., 2016;Wei et al., 2016;Chang et al., 2017). In recent years, acupuncture has been used for treating AD and reported to have effectiveness in improving cognitive function (Jiang et al., 2015;Cao et al., 2017;Ding et al., 2019). However, the possible mechanism of action of acupuncture or EA on cognition in AD patients remains uncertain, limiting the application of these studies to guide clinical practice. ...
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Electroacupuncture (EA) has become popular for its adjustable strength and frequency and easy quantification in the clinic and has demonstrated therapeutic potential for Alzheimer’s disease (AD). However, the mechanism remains unknown. Abnormally activated c-Jun N-terminal kinase (JNK) has been closely related to the pathological process of AD. The aim of this study was to investigate the effect of EA on cognitive impairment and the role of the JNK signaling pathway in AD model amyloid precursor protein (APP)/presenilin 1 (PS1) mice. The memory and learning ability of each group was assessed using the Morris Water Maze (MWM). Immunofluorescence, immunohistochemistry and Western blot were performed to measure the expression of APP, JNK, phosphorylated (P-)JNK, mitogen-activated protein kinase 4 (MKK4), MKK7, c-Jun and caspase-3 in hippocampal tissue samples in APP/PS1 mice after EA intervention. Obvious cognitive deficits were observed in the AD model APP/PS1 mice in the MWM test and were associated with JNK signaling pathway activation and APP upregulation. Four weeks of EA significantly ameliorated the cognitive impairments and inhibited JNK signaling pathway activation and APP upregulation. Taken together, the findings demonstrated that EA can reverse cognitive deficits and substantially lower the burden of APP in AD model APP/PS1 mice, at least partially through inhibiting the JNK signaling pathway and regulating apoptosis signals. Therefore, EA may offer an effective alternative therapeutic approach for AD.
... The selection of the acupoints was based on findings from our previous studies; namely, the therapeutic principle of dredging DU meridian and lighting mind (Jiang et al., 2015(Jiang et al., , 2016(Jiang et al., , 2018Cao et al., 2017;Ding et al., 2019). According to the traditional meridian theory, the DU meridian connects to the brain and is closely associated with all mental activities. ...
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Background The astrocytic phospholipase A2 (PLA2)-arachidonic acid (AA) pathway is crucial in understanding the reduction of cerebral blood flow (CBF) prior to cognitive deterioration. In complementary and alternative medicine, manual acupuncture (MA) is used as one of the most important therapies for Alzheimer’s disease (AD). The beneficial effects of MA on CBF were reported in our previous study. However, the underlying molecular mechanism remains largely elusive.Objective To investigate the effect of MA on the astrocytic PLA2-AA pathway in SAMP8 mice hippocampi.MethodsSAMP8 mice were divided into the SAMP8 control (Pc) group, the SAMP8 MA (Pm) group and the SAMP8 donepezil (Pd) group. SAMR1 mice were used as the SAMRl control (Rc) group. Mice in the Pd group were treated with donepezil hydrochloride at 0.65 μg/g. In the Pm group, MA was applied at Baihui (GV20) and Yintang (GV29) for 20 min. The above treatments were administered once a day for 26 consecutive days. The Morris water maze was applied to assess spatial learning and memory. Immunofluorescence staining, western blot and liquid chromatography-tandem mass spectrometry were used to investigate the expression of related proteins and measure the contents of the metabolic intermediates of the PLA2-AA pathway.ResultsCompared with that in the Rc group, the escape latency in the Pc group significantly increased (p < 0.01); whereas, the platform crossover number and percentage of time and swimming distance in the platform quadrant decreased (p < 0.01). The hippocampal expression of PLA2, cyclooxygenase-1, cytochrome P450 proteins 2C23 and the levels of AA, prostaglandin E2 and epoxyeicosatrienoic acids of the Pc group was drastically higher than that in the Rc group (p < 0.01). These changes were reversed by MA and donepezil (p < 0.01 or p < 0.05).ConclusionMA can effectively improve the learning and memory abilities of SAMP8 mice and has a negative regulatory effect on the PLA2-AA pathway. We propose that the increase of the arterial tone, which is induced by the inhibition of vasodilatory pathway, may be a reason for the beneficial effect of MA on CBF.
Objective To explore the mechanism by which electroacupuncture (EA) upregulates triggering receptor expressed on myeloid cells 2 (TREM2) protein in the hippocampus of Alzheimer’s disease (AD) model animals from the perspective of TREM2 DNA methylation. Methods In total, 24 eight-month-old senescence-accelerated mouse prone 8 (SAMP8) mice were divided into an (untreated) AD group (n = 8), donepezil group (receiving donepezil treatment, n = 8) or EA group (receiving an EA intervention, n = 8). A healthy control group comprising 8-month-old senescence-accelerated mouse resistant 1 (SAMR1) mice (n = 8) was also included. Western blotting, bisulfite sequencing, and oxidative bisulfite sequencing were applied to test the relative expression of TREM2 protein and the methylation levels of the TREM2 gene. Results EA significantly upregulated the relative expression of TREM2 protein (p < 0.01), downregulated the 5-methylcytosine level (p < 0.01) and upregulated the 5-hydroxymethylcytosine level (p < 0.05) in the hippocampus. Conclusion Downregulation of 5-methylcytosine levels and upregulation of 5-hydroxymethylcytosine levels in the TREM2 gene might be the mechanism by which EA promotes the expression of TREM2 protein.
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Alzheimer's disease (AD), as one of most common dementia, mainly affects older people from the worldwide. In this study, we intended to explore the possible mechanism of improving cognitive function and protecting the neuron effect by electroacupuncture. Method: We applied senescence-accelerated mouse prone 8 (SAMP8) mice as AD animal model, used Morris water maze, HE staining, 16S rDNA amplicon sequencing of gut microbiota and ELISA to demonstrate our hypothesis. Results: electroacupuncture improved the learning and memory abilities in SAMP8 mice (P<0.05) and could protect the frontal lobe cortex and hippocampus of SAMP8 mice; electroacupuncture significantly decreased the expression of IL-1β (P<0.01), IL-6 (P<0.01) and TNF-α (P<0.01 in hippocampus, P<0.05 in serum) in serum and hippocampus; electroacupuncture balanced the quantity and composition of gut microbiome, especially of the relative abundance in Delta-proteobacteria (P<0.05) and Epsilon-proteobacteria (P<0.05). Conclusion: electroacupuncture treatment could inhibit the peripheral and central nerve system inflammatory response by balancing the gut microbiota.
Background: Alzheimer's disease (AD) is a neurodegenerative disease, yet there is no effective treatment. Electroacupuncture (EA) is a complementary alternative medicine approach. In clinical and animal studies, EA promotes cognition in AD and vascular dementia. It has been previously reported that cognitive decline in AD might be closely related to reduced glucose intake in the brain. It is worth mentioning that the regions of glucose hypometabolism are usually found to be associated with neuroinflammation. Objective: This study is to explore whether the protective mechanism of EA on cognition is related to the regulation of glucose metabolism and neuroinflammation. Methods: APP/PS1 mice were randomly divided into AD group and the treatment (AD + EA) group. In the AD + EA group, EA was applied on Baihui (GV20) and Yintang (GV29) for 20 min and then pricked at Shuigou (GV26), once every alternate day for 4 weeks. Morris water maze (MWM) tests were performed to evaluate the effects of EA treatment on cognitive functions. 18F-FDG PET, immunofluorescence, and western blot were used to examine the mechanisms underlying EA effects. Results: From MWM tests, EA treatment significantly improved cognition of APP/PS1 mice. From the 18F-FDG PET, the levels of uptake rate of glucose in frontal lobe were higher than the AD group after EA. From immunofluorescence and western blot, amyloid-β (Aβ) and neuroinflammation were reduced after EA. Conclusion: These results suggest that EA may prevent cognitive decline in AD mouse models by enhancing glucose metabolism and inhibiting inflammation-mediated Aβ deposition in the frontal lobe.
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Background Cumulating evidence has revealed the effectiveness of acupuncture therapy in relieving pain via immunoregulation. However, its underlying mechanism remains unknown. The present study was designed to determine the changes of immunogenic responses at different time-points of electroacupuncture (EA) interventions in neuropathic pain rats. Methods The neuropathic pain model was established by ligature of the left sciatic nerve to induce chronic constriction injury (CCI). EA was applied at Zusanli (ST36) and Yanglingquan (GB34) for the EA groups. The thermal pain threshold was detected with an algesia-detector. The subgroups of plasma and splenic lymphocytes were determined via fluorescence-activated cell sorting. Specific inflammatory cytokines were assayed using an ELISA-based bead multiplex assay. The activities of splenic natural killer (NK) cells and cytotoxic T lymphocytes were detected by methyl thiazolyl tetrazolium colorimetric method. For confirming the involvement of NK cell in EA-analgesia, anti-asialo-ganglio-N-tetraosylceramide (anti-asialo-GM1) antibody was given to CCI rats before EA. Results Following CCI, the thermal pain threshold of the affected hind footpad was significantly decreased, and increased from the 3rd day to the 12th day after EA interventions, presenting a time-dependent tendency from the 5th day on. From day 3 to 5 of EA interventions, the percentages and activity of splenic NK cells, concentrations of splenic interleukin-2 (IL-2) and beta-endorphin (β-EP) were significantly increased. Meanwhile, the concentrations of plasma IL-2, IL-1β and gamma-interferon (IFN-γ) were significantly decreased and returned to the normal level on day 12 following EA. Plasma transforming growth factor-β (TGF-β) levels were considerably upregulated on day 5 and 12 following EA. The CD4+/CD8+ T cell ratio was markedly downregulated compared with the control and CCI groups on day 5 and returned to the normal level on day 12 following EA. After depleting NK cells by anti-asialo-GM1 antibody, the increased thermal pain threshold following EA intervention was obviously reduced. Conclusions Repeated EA interventions have a time-dependent cumulative analgesic effect in neuropathic pain rats, which is closely associated with its regulatory effects on NK cells, splenic IL-2, β-EP, and plasma IL-2, IL-1β, IFN-γ and TGF-β levels.
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Background. Extracorporeal shock wave lithotripsy (ESWL) is the preferred option for urolithiasis treatment. However, intensities of pain may be induced and the sedative anesthetic or analgesics were usually needed. The aim of this study was to develop an improved acupuncture-assisted anesthesia approach in pain relief. Methods. We conducted a single-blind, randomized controlled study in China Medical University Hospital. Patients treated by ESWL due to upper urolithiasis were randomly divided into control group, sham-EA group, and 100 Hz EA group. The high frequency electroacupuncture (EA) was applied at the Weizhong acupoint (100 Hz EA group) for 20 minutes prior to the ESWL. In the sham-EA group, the same procedures were performed as those of 100 Hz EA group but no electric current was given to stimulate the acupoints. In the control group, no action was taken before operation. The information including the numbers and dosage of analgesic requirements, pain score, vital signs, and the satisfaction of procedure was collected. Results. A total of 74 subjects were recruited and we found that the interval to the first request analgesic, the number/total dosage of additional analgesic, recovery time from anesthesia, and the satisfaction were all better in both the 100 Hz EA and the sham-EA group. The 100 Hz EA also showed better relief of painful sensations by delaying the onset of pain. Conclusions. The 100 Hz EA and the sham-EA can effectively relieve pain due to ESWL as well as reducing the dosage of opium analgesic used.
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Electroacupuncture (EA) treatment has been widely used for stroke-like disorders in traditional Chinese medicine. However, the underlying mechanisms remain unclear. Our previous studies showed that single-time EA stimulation at “Baihui” (GV 20) and “Shuigou” (GV 26) after the onset of ischemia can protect the brain against ischemic injury in rats with middle cerebral artery occlusion (MCAO). Here, we further investigated the differential effects between multiple EA and single-time EA stimulation on ischemic injury. In the present study, we found that both single-time EA and multiple EA stimulation significantly reduced MCAO-induced ischemic infarction, while only multiple EA attenuated sensorimotor dysfunctions. Also, with PCR array screening and ingenuity gene analysis, we revealed that multiple EA and single-time EA stimulation could differentially induce expression changes in neurotrophic signaling related genes. Meanwhile, with western blotting, we demonstrated that the level of glia maturation factor β (GMF β ) increased in the early stage (day 1) of reperfusion, and this upregulation was suppressed only by single-time EA stimulation. These findings suggest that the short-term effect of single-time EA stimulation differs from the cumulative effect of multiple EA, which possibly depends on their differential modulation on neurotrophic signaling molecules expression.
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Strategies to develop effective neuroprotective therapy to reduce brain damage and related behavioral deficits in stroke patients are of great significance. Electroacupuncture (EA), which derives from traditional Chinese medicine, may be effective as a complementary and alternative method for promoting recovery of neurological function and quality of life. Adult Sprague-Dawley rats were randomly divided into 3 groups: (1) sham, (2) middle cerebral artery occlusion (MCAO) model groups of 2 h MCAO followed by 1, 3, 5, or 7 d of reperfusion, and (3) EA groups of 2 h MCAO followed by 1, 3, 5, or 7 d of reperfusion. EA groups received EA therapy by needling at GV20 and left ST36. The results show that EA therapy improved the neurological function and reduced infarct volume, confirmed by modified neurological severity scores and TTC staining. Real-time PCR, immunohistochemistry, and western blot assay verified that EA upregulated the expression of tight junction (TJ) claudin-5, occludin, and zonula occluding-1 from 1 to 7 d after reperfusion. Our findings suggest that EA reduces brain damage and related behavioral deficits via upregulation of the TJ proteins.
Alzheimer's disease (AD) is the most common form of dementia in the elderly. The number of people affected by AD is rapidly increasing. AD is characterized by cerebral atrophy, cerebral senile plaques, intraneuronal neurofibrillary tangles, and neuronal cell loss. Medical treatment of AD has a long history and differing results. We will review the effectiveness and limitations of the drugs used to treat AD. © 2012, International Research and Cooperation Association for Bio & Socio-Sciences Advancement. All rights reserved.
Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity following chronic constriction injury, es-pecially electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function.
Objective To investigate the effects and mechanisms of action of auricular electroacupuncture (AEA) on visceral pain induced by colorectal distension (CRD). Methods Twenty-nine female Sprague-Dawley rats were randomly divided into four groups: control; untreated CRD; CRD+AEA; and CRD+sham electroacupuncture (SEA). An electromyogram (EMG) was recorded for 120 min in the conscious state. After a 30 min baseline recording, CRD was performed in untreated CRD, AEA and SEA groups and lasted for 90 min. AEA and SEA were started at 30 min and lasted for 30 min. The EMG was recorded and analysed to evaluate the severity of visceral pain, indicated by the magnitude of the vasomotor response (VMR). mRNA expression of the 5-hydroxytryptamine 1a (5-HT1a) receptor was measured separately in the colon and raphe nuclei using real-time fluorescent quantitative PCR. Results No differences were seen in the baseline EMG among the four groups (p>0.05). During pre-stimulation, VMR magnitude in the CRD, AEA and SEA groups increased compared with that in the control group (p<0.05). During stimulation, the VMR magnitude was significantly decreased in AEA but not SEA groups relative to the (untreated) CRD group. Similarly, mRNA expression of the 5-HT1a receptor in both the colon and raphe nuclei was lower in AEA but not SEA groups compared with the CRD group (p<0.05). Conclusions AEA can ameliorate CRD-induced visceral pain in rats, and increase mRNA expression of the 5-HT1a receptor peripherally (in the colon) and centrally (in the raphe nuclei), suggesting a serotonergic mechanism of action.
The study investigated the role of nucleus tractus solitarius (NTS) neurons in electroacupuncture (EA) analgesia in colorectal distension (CRD) rats. NTS neurons responding to both CRD test and EA conditioning stimulations were considered somato-visceral convergent neurons. The neuronal activities evoked by graded CRD showed multiple firing patterns indicating multisynaptic connections. Some of the CRD excitatory neurons were inhibited by EA and vice versa. There was no discrepancy among different acupoints in inducing the changes of unit discharges. Conclusively, EA could regulate CRD related neurons in the NTS through polysynaptic cross-talk, which mediates EA analgesia on visceral pain in anesthetized rats.
Background Although electroacupuncture (EA) is effective in the relief of neuropathic pain, the underlying mechanisms remain unclear. Previous studies have reported immunomodulatory effects of EA in rats. Since excessive release of interferon-γ (IFN-γ) after nerve injury transforms quiescent spinal microglia into an activated state with more neuropathic pain, associated with purinergic receptor P2X4 expression, it is possible that EA may mediate its analgesic effect by attenuating IFN-γ release and subsequent generation of P2X4R+ microglia.
P2X is a family of ligand-gated ion channels that act through adenosine ATP. The P2X3 receptor plays a key role in the transmission of neuropathic pain at peripheral and spinal sites. Electroacupuncture (EA) has been used to treat neuropathic pain effectively. To determine the role of EA in neuropathic pain mediated through the P2X3 receptor in dorsal root ganglion neurons and the spinal cord, a chronic constriction injury (CCI) model was used. Sprague-Dawley rats were divided into four groups: sham CCI, CCI, CCI plus contralateral EA, and CCI plus ipsilateral EA. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded. Furthermore, the expression of the P2X3 receptor was evaluated through Western blotting and immunofluorescence. The effects of EA and A-317491 were investigated through the whole-cell patch-clamp method and intrathecal administration. Our results show that the MWT and TWL of EA groups were higher than those in the CCI group, whereas the expression of the P2X3 receptor was lower than that in the CCI group. However, no significant difference was detected between the two EA groups. EA depressed the currents created by ATP and the upregulation of the P2X3 receptor in CCI rats. Additionally, EA was more potent in reducing mechanical allodynia and thermal hyperalgesia when combined with A-317491 through intrathecal administration. These results show that both contralateral and ipsilateral EA might inhibit the primary afferent transmission of neuropathic pain induced through the P2X3 receptor. In addition, EA and A-317491 might have an additive effect in inhibiting the transmission of pain mediated by the P2X3 receptor. © 2014 Wiley Periodicals, Inc.