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Review ArticleCentral and Peripheral Mechanism of Acupuncture Analgesia onVisceral Pain: A Systematic Review
In-Seon Lee ,1 Soyeon Cheon ,2 and Ji-Yeun Park 3
1National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda 20892, USA2Department of Public Health, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan3College of Korean Medicine, Daejeon University, Daejeon 34520, Republic of Korea
Correspondence should be addressed to Ji-Yeun Park; [email protected]
Received 13 November 2018; Revised 12 March 2019; Accepted 26 March 2019; Published 2 May 2019
Academic Editor: Gerhard Litscher
Copyright © 2019 In-Seon Lee et al. This 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.
Background/Aims. Despite the wide use of acupuncture for the management of visceral pain and the growing interest in thepathophysiology of visceral pain, there is no conclusive elucidation of themechanisms behind the effects of acupuncture on visceralpain. This systematic review aims to provide an integrative understanding of the treatment mechanism of acupuncture for visceralpain. Methods. Electronic and hand searches were conducted to identify studies that involved visceral pain and acupuncture.Results.We retrieved 192 articles, out of which 46 studies were included in our review. The results of our review demonstrated thatvisceral pain behaviors were significantly alleviated in response to acupuncture treatment in groups treated with this interventioncompared to in sham acupuncture or no-treatment groups. Changes in the concentrations of 𝛽-endorphin, epinephrine, cortisol,and prostaglandin E2 in plasma, the levels of c-Fos, substance P, corticotropin-releasing hormone, P2X3, acetylcholinesterase(AchE), N-methyl-D-aspartate (NMDA) receptors, and serotonin in the gut/spinal cord, and the neuronal activity of the thalamuswere associated with acupuncture treatment in visceral pain.Conclusions.Acupuncture reduced visceral pain behavior and inducedsignificant changes in neuronal activity as well as in the levels of pain/inflammation-related cytokines and neurotransmitters in thebrain-gut axis. Further researches on the thalamus and on a standard animal model are warranted to improve our knowledge onthe mechanism of acupuncture that facilitates visceral pain modulation.
1. Introduction
Visceral pain, i.e., pain originating from the thoracic, abdom-inal, or pelvic regions, is a noticeable symptom associatedwith various clinical conditions [1, 2]. Visceral pain has dif-ferent characteristics compared to somatic pain. The formeris diffusely localized, not evoked by entire viscera, and rarelylinked to actual injuries. Although there has been grow-ing interest in the mechanisms and factors that contributeto the pathogenesis of visceral pain, many researches arestill more focused on somatic pain [3]. To date, severalunderlying causes of visceral pain have been proposed,e.g., visceral hypersensitivity due to sensitized visceral noci-ceptors/afferent fibers, impairments of the brain-gut axis,referred hyperalgesia from viscerosomatic convergence in thespinal cord and central nervous system (CNS), infections,psychological and genetic factors, and hormonal changes
[1, 3, 4]. Moreover, a major advance in the understandingof the central mechanisms and the gut environment (e.g.,microbiota) of humans has suggested that the brain-gutaxis plays a crucial role in visceral nociception in termsof neuronal/chemical signaling between the brain and thegastrointestinal tract [5, 6].
Acupuncture has been used to treat various pain disor-ders, including visceral pain, and has shown considerableeffects on pain relief with only rare cases of adverse events.Many studies have explored the treatment mechanism ofacupuncture for pain relief in general, and it is reported thatacupuncture alleviates pain mainly by regulating the levelsof endogenous opioids, serotonin, and norepinephrine andby inhibiting visceral nociceptors, inflammatory cytokines,and CNS activation [7–9]. Furthermore, acupuncture candecrease visceral sensitivity [10], activate the enteric nervoussystem (ENS) [11], and modulate the brain-gut axis [12].
HindawiEvidence-Based Complementary and Alternative MedicineVolume 2019, Article ID 1304152, 22 pageshttps://doi.org/10.1155/2019/1304152
2 Evidence-Based Complementary and Alternative Medicine
Table 1: Search terms used in each database.
Database Search terms
PUBMED(acupuncture [MeSH Terms] OR acupuncture [All Fields] OR acupoint [All Fields] OR electroacupuncture[MeSH Terms] OR electroacupuncture [All Fields]) AND (“visceral pain” [MeSH Terms] OR “visceral pain”[All Fields] OR (visceral [All Fields] AND (pain [All Fields] OR pain [MeSH Term])) OR (visceral [All Fields]AND (hyperalgesia [All Fields] OR hyperalgesia [MeSH Terms])))
EMBASE visceral AND (“pain”/exp OR pain OR “hyperalgesia”/exp OR hyperalgesia OR algesia) AND(“acupuncture”/exp OR acupuncture OR “electroacupuncture”/exp OR electroacupuncture OR acupoint)
MEDLINE (visceral and (pain or hyperalgesia or algesia) and (acupuncture or electroacupuncture or acupoint)).mp.Cochrane Library visceral AND (pain OR hyperalgesia OR algesia) AND (acupuncture OR electroacupuncture OR acupoint)
However, the treatment mechanism behind the effects ofacupuncture on visceral pain is still unclear [4, 9], partiallydue to the lack of a systematic approach that encompasses awide range of evidence from basic and clinical researches toanalyze this aspect.
In this review, we aimed to provide an integrative under-standing of themechanisms behind the effects of acupuncturetherapy on visceral pain in both human and animal subjects,and we suggest directions that can be adopted for futureresearch.
2. Methods
2.1. Search Strategy. We searched through electronic recordsin PubMed, EMBASE, MEDLINE, and the Cochrane Libraryusing the keywords “visceral,” “pain,” “hyperalgesia,” “alge-sia,” “acupuncture,” “electroacupuncture,” and “acupoint.”The search terms and strategies were modified for eachindividual database (Table 1). Hand searching was performedby screening the reference lists of articles that met ourinclusion criteria. The literature search was completed inSeptember 2017, and our search strategy was in compliancewith the PreferredReporting Items for Systematic Review andMeta-Analyses (PRISMA) guidelines for systematic reviews.
2.2. Study Selection. Search results were screened based onthe titles and abstracts before full text assessments. Weincluded original studies that investigated the therapeuticeffects and/or the mechanisms of acupuncture on visceralpain. Both animal and human studies written in Englishor Chinese were included. In this review, we consideredmanual acupuncture (MA), electroacupuncture (EA), tran-scutaneous electrical nerve stimulation on acupoints (acu-TENS), pharmacopuncture (injection of herbalmedicine intoacupoints, e.g., sweet bee venom), and laser acupuncture (LA)techniques as the different types of acupuncture.
2.3. Risk of Bias Assessment in the Human Studies. Concern-ing the studies on human subjects, we evaluated the risk ofbias associated with each of them using either the revisedCochrane risk of bias tool for randomized trials (RoB 2.0 [13])or the Risk Of Bias In Nonrandomized Studies (ROBINS-I [14]) based on each study design, with a focus on thepain-related outcomes. More details on the assessments aredescribed in the footnotes of supplementary Tables 1 and 2.
3. Results
3.1. Search Results. Our search strategy resulted in theretrieval of 192 articles in total. Following this, in additionto removing the duplicates (n=35), 111 studies were excludedbased on their titles and abstracts. Among the excluded stud-ies, 67 studies were unrelated to visceral pain or acupuncture,28 studies were not original, and 11 studies were writtenin languages other than English or Chinese. Further, fulltexts corresponding to four studies, each published before1990, could not be obtained, and one study was retracted.Ultimately, 46 articles were included in this review (Figure 1).
3.2. Visceral Pain Studies on Humans
3.2.1. Visceral Pain Patients and Healthy Participants. Therewere seven studies with human subjects. Two studiesincluded irritable bowel syndrome (IBS) patients [15, 16], andone study involved primary dysmenorrhea [17] and anotherstudy involved chronic pancreatitis patients [18]. Further, astudy by Kotani et al. [19] investigated postoperative visceralpain in patients who underwent upper or lower abdominalsurgeries [18], and two studies involved healthy participants[20, 21] (Table 2).
3.2.2. Details of Acupuncture Interventions. Among the sevenstudies conducted on humans, the various types of acupunc-ture techniques that were used are as follows: MA in fourstudies [17–19, 21], acu-TENS in three studies [16, 17, 20], andEA in two studies [15, 17]. Most of these studies described thestimulation method that was used, the intensity (frequency,voltage, and amperage), and the locations of acupoints.The acupoints that were used in the human studies aresummarized in Figure 2(a).
3.2.3. Outcomes and Results
(1) Pain Behavioral Outcomes. In human studies, improve-ments in the pain behavioral outcomes have been consis-tently observed after acupuncture treatment. Acupuncturetreatment showed significantly greater analgesic effects basedon subjective pain ratings than sham acupuncture [16, 18, 19],and the maximum tolerable rectal sensation and distentionpressure in IBS patients were significantly increased by acu-TENS compared to sham TENS [20] (Tables 2 and 5).
Evidence-Based Complementary and Alternative Medicine 3
Table2:Overviewof
visceralpain
studies
onhu
mans.
Author
(year)
Participantsgrou
p:n(f)/
meanage
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
acup
oints
number,du
ratio
nCon
trol
acup
oints
number,du
ratio
n
(1)Th
omas
etal.(1995)[17]
Prim
arydysm
enorrhea
Acu:17(17)/30.4
Con
:12(12)/27.8
(a)M
A(b)E
A(2Hz)
(c)E
A(100Hz)
(d)P
erioste
alstim
ulation
(e)a
cu-TEN
S(2Hz)
(f)a
cu-TEN
S(100Hz)
(a),(b),(c),(d):
BL32,C
V4,SP
6,9
(e),(f):Spinou
sprocesses
Thoracic
10-Lum
bar1
2,20min
(g)S
ham
TENS
(ns)
Spinou
sprocesses
Thoracic
10-Lum
bar1
2,20min
(1)B
lood
loss
(2)V
omiting
(3)W
orkho
urslost
(4)T
abletintake
(5)S
ubjectivea
ssessm
ent
(6)T
otalpain
With
ingrou
p(4),(5),(6)(a),(c),(d)
improved
(5),(6)(b)
improved
(4),(5),(6)(e)im
proved
(2)K
otaniet
al.(2001)[19]
(1)U
pper
abdo
minal
surgery
(A)5
0(21)/52
(C)4
8(18)/55
(2)L
ower
abdo
minal
surgery
(B)3
9(12)/55
(D)3
8(13)/55
(A)P
atient
1+MA
(B)P
atient
2+M
A
(A)B
L18,19,20,
21,22,23,24
(B)B
L20,21,22,
23,24,25,26
1,4days
(C)P
atient
1+sham
MA(ni)
(D)P
atient
2+sham
MA(ni)
(C)B
L18,19,20,
21,22,23,24
(D)B
L20,21,22,
23,24,25,26
1,4days
(1)Incision
al,visc
eralpain
(2)D
rowsin
ess
(3)P
ruritus
(4)N
ausea/Vo
miting
(5)A
dequ
acyof
pain
treatment
(6)M
orph
ineintake
(7)A
drenalho
rmon
e
With
ingrou
p(1)(A),(C
)improved
(6)(A),(B),(C
),(D
)decreased
Betweengrou
ps(1),(4),(6),(7)(epinephrine,
cortiso
l)(A
)<(C
),(B)<(D
)
(3)X
ingetal.
(200
4)[16]
IBS
+rectald
istentio
n7(6)/44
(a)a
cu-TEN
S(5Hz,
250m
s)(a)S
T36,PC
61,-
(b)T
ENS(5Hz,
250m
s)(b)n
on-acupo
int
1,-
(1)R
ectalton
e(2)R
ectalcom
pliance
(3)R
ectalp
erceptionof
gas,
pain,desire
todefecate
With
ingrou
p(1)(A),(B)d
ecreased
(3)(A)d
ecreased
Betweengrou
ps(3) (A)<(B)
(4) C
huetal.
(2012)
[15]
IBS
+rectald
istentio
n(A
)15(7)/42.3
(B)15(8)/44.2
(A)E
A(10H
z,0.5m
s,60v)
(A)S
T36,37,SP6
2,30min
(B)S
ham
EA(ns)
(B)S
T36,37,SP6
2,30min
(1)fMRI-rectald
istentio
n(2)fMRI-A
orB+rectal
diste
ntion
(3)fMRI-rectald
istentio
naft
er(2)
(4)fMRI-A
orB
(5)R
ectalsensatio
n
With
ingrou
p(1)(A),(B):AC
C,pgCC
,PF
C,TH
,INS,cerebellu
m,
Temp
(A):(1)<(2)p
gCC,
ACC,
PFC,
SC,INS,Temp
(1)<(3)P
FC,SC,
Temp
(3)<(2)A
CC,P
FC,T
H,INS,
Temp
(B):(2)>(1)A
CC,P
FC,SC
(3)>(1)P
FC,Tem
p,cerebellu
m(2)>(3)T
emp
(3)>(2)P
FCBe
tweengrou
ps(A
)>(B):(2)>(1)inTH
,INS
Correlationbetween(5)a
ndbrainactiv
ationin
hypo
thalam
us,T
H,INS
4 Evidence-Based Complementary and Alternative Medicine
Table2:Con
tinued.
Author
(year)
Participantsgrou
p:n(f)/
meanage
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
acup
oints
number,du
ratio
nCon
trol
acup
oints
number,du
ratio
n
(5)L
eung
etal.(2013)[20]
Health
y+rectald
istentio
n(A
)20(12)/53.4
(B)2
0(12)/53.9
(A)a
cu-TEN
S(2Hz,
0.2m
s)
(A)L
I4,P
C6,
ST36
1,45min
(B)S
ham
TENS
(ns)
(B)L
I4,P
C6,
ST36
1,45min
(1)T
olerance
torectal
sensation
(2)R
ectald
istentio
npressure
(3)B
eta-endo
rphin
Betweengrou
ps(1),(2),(3)(B)<(A
)
(6)Jueletal.
(2016)
[21]
Health
y+rectald
istentio
n15(8)/27.6
(a)M
A
(a)C
V4,6,7,9,
10,12,ST
25,26,
37,LI4
+non
-acupo
ints
1,30min
(b)S
ham
MA(ni)
(b)S
T37,LI4
1,30min
(1)R
ectald
istentio
nvolume
(2)R
ectalp
ain
(3)E
EG
With
ingrou
ps(1)(A),(B)increased
(7)Jueletal.
(2017)
[18]
Chronicp
ancreatitis
15(7)/61.8
(a)M
A
(a)C
V4,6,9,10,
12,ST2
5,ST
36,
SP6,8,9,
15+n
on-acupo
ints
1,-
(b)S
ham
MA(ni)
(b)C
V4,6,9,10,
12,ST2
5,ST
36,
SP6,8,9,
15+n
on-acupo
ints
1,-
(1)R
educed
pain
score
(2)E
EGBe
tweengrou
ps(1)(B)<(A
)
Group
writtenin
lowercaselette
rs(e.g.,(
a),(b),and
(c)):differenttreatmentsin
thesam
epop
ulation,un
lessstated
otherw
ise;G
roup
writtenin
capitalletters(e.g.,(
A),(B),and(C
)):differenttreatmentsin
different
popu
latio
nAc
u:acup
uncturegrou
p;AC
C:anterio
rcingulatecortex;B
L:BladderM
eridian;
Con
:con
trolg
roup
;CV:
Con
ceptionVe
sselMeridian;
EA:electro-acupu
ncture;E
EG:electroenceph
alograph
y;f:female;fM
RI:
functio
nalm
agnetic
resonanceimaging;IBS:irr
itableb
owelsynd
rome;IN
S:insula;LI:LargeIntestin
eMeridian;MA:m
anualacupu
ncture;n:num
ber;ni:notinserted;ns:no
tstim
ulated;PC:
Peric
ardium
Meridian;
PFC:
prefrontalcortex;pgC
C:perig
enualcingulatec
ortex;SC
:som
atosensory
cortex;SP:Spleen
Meridian;ST
:StomachMeridian;Temp:tempo
rallob
es;T
H:thalamus;(acu-)TEN
S:Transcutaneous
electric
alnerve
stimulation(onacup
oints);m
in:m
inutes;m
s:millise
cond
s;v:volts.
Evidence-Based Complementary and Alternative Medicine 5
192 records identified through database/hand searching
157 records a�er duplicates removed
46 full -text articles assessed for eligibility
46 studies included in qualitative synthesis
111 records excluded based on the title and abstract with reasons
o Not visceral pain study (n=38)o Not acupuncture study (n=29)o Not original study (n=28)o Not written in English or Chinese (n=11)o Retracted (n=1) o Full -text not available (n=4)
Figure 1: Flow diagram of article inclusion.
ST36
CV4
CV6
CV9
CV10
CV12SP6PC6
SP9ST25
SP26
BL18-26,BL32, SP8, ST37, LI4
Human
n=4
n=3
n=2
n=1
(a) (b)
ST36
ST37CV12
SP6Aur
EX-B2PC6ST2ST25
TE5
Animal
n=27
n=11
n=3
n=2
n=1
CV24, GB14, GB31, GB34,
GV26, LI11, LR3,Lumb, ST6
Figure 2: Frequency distribution of acupuncture points in the human and animal studies on visceral pain. Acupuncture points on StomachMeridian (ST) and Conception Vessel Meridian (CV) are most frequently selected for visceral pain. Aur: auricular acupoints, Lumb: lumbaracupuncture points, n: number of studies reporting the acupuncture points, BL: Bladder Meridian, GB: Gallbladder Meridian, LI: LargeIntestine Meridian, LR: Liver Meridian, PC: PericardiumMeridian, SP: Spleen Meridian, and TE: Triple Energizer Meridian.
(2) Metabolic Outcomes. In human studies, the secretion of𝛽-endorphin increased after acu-TENS [20], and the levels ofadrenal hormones [19] and serum prostaglandin E2 (PGE2)[22] were decreased after MA. The plasma levels of 𝛽-endorphin were increased after EA [23] (Tables 2 and 5,Figure 3).
(3) Brain and Brain Stem. Functional magnetic resonanceimaging (fMRI) and electroencephalography (EEG) wereused to measure neuronal activity in IBS patients [15] andhealthy participants [18, 21].The fMRI results showed signifi-cant increases in the brain activity in the thalamus and insulain the EA group compared to in the sham EA group [15], and
6 Evidence-Based Complementary and Alternative Medicine
Animal Human
Acupuncture
DRN
MED
TH
HyTH
PFCACC
INS PAG4th V
Acupuncture
DRGCCDH
• Neural activity• Inflammatory-biomarkers
(p38, P2X3, NR2B)
Spinal cord
• Neural activity• Pain excitation neurons• Stress related hormones• Pain inhibitory neurons• Endogenous opioid
neurotransmitters
Brain
• Intrinsic inflammatory biomarkers (c-Fos, p38, sub P, P2X3)
• Serotonin and endogenous opioid neurotransmitters
Gut
THPAG
SCACC
PFC
AMG
INS
Figure 3: Schematic illustration of functional andmetabolic changes (peptides, proteins, andmRNA) of the brain-gut axis by acupuncture invisceral pain studies. In human, acupuncture consistently enhanced the functional activity in the thalamus and insula, the core brain regionsof pain processing. In animal, a great variety of metabolic changes have been reported as well as functional neural activities, demonstratingthat acupuncture induces a wide range of changes through the brain-gut axis in visceral pain. ACC: anterior cingulate cortex; AMG: amygdala;CC: central canal; DH: dorsal horn; DRG: dorsal root ganglion; DRN: dorsal raphe nucleus; HyTH: hypothalamus; INS: insula; MED:medulla; NR2B: N-methyl-D-aspartate receptor subunit; PAG: periaqueductal gray; PFC: prefrontal cortex; P2X3: P2X purinoceptor 3; SC:somatosensory cortex; sub P: substance P; TH: thalamus; 4th V: fourth ventricle.
therewere no significant differences observed in the EEGdatabetween the groups [18, 21] (Tables 2 and 5, Figure 3).
3.2.4. Risk of Bias in the Human Studies. There were threerandomized parallel-group trials [15, 19, 20] and two ran-domized cross-over trials [18, 21] included in our review. Onestudy reported results from two different groups (acupunc-ture and acu-TENS), and within each group, the assignmentof the different interventions to the patients was randomized[17]. Therefore, we treated this study as two randomizedcross-over studies and assessed the risk of bias associatedwitheach group separately. Lastly, one studywas a nonrandomizedtrial. The results of the assessments of each domain’s risk ofbias and the overall risk of bias are presented in Supplemen-tary Tables 1 and 2 for the randomized and nonrandomizedstudies, respectively.
Out of the seven studies, three studies were classified ashaving low overall risks of bias. Further, two randomizedstudies [17, 20] were considered as having high risks of biasdue to concerns regarding possible selective reporting.More-over, there were some concerns regarding three randomizedstudies [17, 18, 21] with regard to randomization domainsbecause they lacked information regarding either their ran-dom sequence generation or their allocation concealment;therefore, we labeled these studies as “some concerns.”Lastly, there were some concerns regarding missing data
associatedwith two studies because they did not provide clearindications on whether the results that were summarized inthe texts or figures were from all the study participants.
3.3. Visceral Pain Studies on Animals
3.3.1. Visceral Pain Models. We found 39 studies that exam-ined various visceral pain models in animals. Thirty-onestudies used rats [10, 23–51], and the remaining used cats[52–54], mice [22, 55, 56], rabbit [57], or dog [58]. Toinduce visceral pain, mechanical stimulation by colorec-tal/rectal/gastric distention was most commonly used (n=19)[10, 24, 25, 28, 29, 32, 33, 35–41, 44, 45, 47, 51, 58]. Othermeth-ods included splanchnic nerve stimulation [48, 52–54, 57],acetic acid injections [22, 23, 31, 55, 56] (n=5, respectively),somatic and visceral noxious stimuli [49], formalin injection[23], and antimony potassium tartrate injection [50] (Tables3 and 4).
3.3.2. Details of Acupuncture Interventions. Further, concern-ing the animal studies, EA was the intervention that was usedin most of them [10, 23, 25–29, 31–43, 45, 47–54, 57, 58](n=32), and the others involved MA [22, 24, 44, 55], LA[30, 46], or pharmacopuncture techniques using bee venom[56] or snake venom [23].The acupoints that were used in theanimal studies are summarized in Figure 2(b).
Evidence-Based Complementary and Alternative Medicine 7
Table3:Visceralhypersensitivity
mod
elsinanim
alstu
dies
(visc
eralhypersensitivity
andCR
Dmod
els).
Author
(year)
Mod
el(animal,gender,nu
mber)
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
acup
oints
number,du
ratio
nCon
trol
acup
oints
number,du
ratio
n
(1)C
uietal.
(2005)
[25]
Visceral
hypersensitivity
+CRD
(SDrat,m,various)
(A)M
odel+E
A(4/10
0Hz,1m
A)
(A)S
T36,37
7,30min
(B)C
ontro
l(C
)Mod
el(D
)Mod
el+S
ham
EA(ns)
(A)S
T36,37
7,30min
(1)A
WR
(2)A
ctivity
ofrectus
abdo
minis
Betweengrou
ps(1),(2)(A)<(C
),(B)<(C
)
(2)T
ianetal.
(200
6)[26]
(1)C
olorectal
irritatio
n-indu
cedvisceral
hypersensitivity
(SDrat,
m,6/group
)(2)M
odel1+str
ess
(A)M
odel1+EA
(2Hz,0.3m
A)
(B)M
odel2+
EA(2Hz,0.3m
A)
(A),(B)S
T36,
SP6
1,30min
(C)C
ontro
l(D
)Mod
el1
(E)M
odel2
-
(1)A
WR
(2)P
ainthreshold
pressure
(3)F
ecalpellet
(4)5
-HT4
areceptorin
colon
(5)S
eroton
intransporter
incolon
Betweengrou
ps(1)(A),(C
)<(D
)(2)(D)<(A
),(C
)(3)(B),(C)
,(D)<(E)
(4),(5)(B)<(A
),(C
)(5)(D)<(C
)
(3)L
iuetal.
(200
9)[27]
Visceralhypersensitivity
(SDrat,m,8/group
)
(A)M
odel+E
A(2/10
0Hz,
0.2–0.6m
s,1m
A)
(A)S
T25,ST
377,20min
(B)C
ontro
l(C
)Mod
el-
(1)A
WR
(2)C
oncentratio
nof
5-HT
(3)C
oncentratio
nof
5-HT3
R(4)C
oncentratio
nof
5-HT4
R
Betweengrou
ps(1),(2)(A),(B)<(C
)(4)(C)<(A
),(B)
(4)X
uetal.
(200
9)[10]
Visceralhypersensitivity
+CRD
(SDrat,m,
6-25/group
total74)
(A)M
odel+E
A(2/10
0Hz,0.1m
s,1m
A)
(B)
Mod
el+EA
+SAL
(sam
easa
bove)
(A),(B)S
T36
5,40
min
(C)C
ontro
l(D
)Mod
el(E)M
odel+S
ham
EA(ns)
(F)M
odel+E
A+N
AL
(E),(F)S
T36
5,40
min
(1)V
MR
(2)M
embranep
otentia
lof
DRG
neuron
(3)R
heob
aseo
fDRG
neuron
(4)A
ctionpo
tentialof
DRG
neuron
With
ingrou
p(1)(D):increased
(1)(A),(B):decreased
after
treatment(effect
blockedin
(F))
Betweengrou
ps(2)(A)<(E),(C
)<(D
)(3)(D)<(C
),(E)<(A
)(4)(A),(C
)<(D
)
(5)W
uetal.
(2010)
[29]
Visceralhypersensitivity
+CRD
(SDrat,m,
8/grou
p)
(A)M
odel+E
A(10H
z,0.18ms,
∼3m
A)
(A)S
T36
3,20min
(B)C
ontro
l(C
)Mod
el+S
ham
EA(ns)
(B)S
T36
3,20min
(1)P
ainthresholdto
CRD
(2)V
MR
(3)5
-HTin
colon,
spinal
cord,brainste
m(4)c-Fos
incolon,
spinal
cord,brainste
m
Betweengrou
ps(1)(C)<(A
),(B)
(2),(3),(4)(A),(B)<(C
)(except(3)
incolon)
(B)<(A
)(in
40,60,
80mmHg)
8 Evidence-Based Complementary and Alternative Medicine
Table3:Con
tinued.
Author
(year)
Mod
el(animal,gender,nu
mber)
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
acup
oints
number,du
ratio
nCon
trol
acup
oints
number,du
ratio
n
(6)Q
ietal.
(2012)
[32]
Visceralhypersensitivity
+CRD
(SDrat,m,
8/grou
p)
(A)M
odel+E
A(5/10
0Hz)
(A)S
T36,37
4,30min
(B)C
ontro
l(C
)Mod
el(D
)Mod
el+sham
EA(ns)
(D)S
T36,37
4,30min
(1)P
ainthresholdpressure
(2)A
WR
(3)c-Fos
inRV
M(4)N
-methyl-D
-aspartate
receptor
1inRV
M
With
ingrou
p(2)(A):decreasedaft
ertre
atment
Betweengrou
ps(1)(C)<(A
),(B)
(2)(B)<(C
)(3)(A)<(C
)(4)(A),(B)<(C
)
(7)Q
ietal.
(2012)
[33]
Visceralhypersensitivity
+CRD
(SDrat,m,
8/grou
p)
(A)M
odel+E
A(5/10
0Hz)
(A)S
T36,37
4,30min
(B)C
ontro
l(C
)Mod
el(D
)Mod
el+sham
EA(ns)
(D)S
T36,37
4,30min
(1)A
WR
(2)c-Fos
inspinalcord
Betweengrou
ps(1),(2)
(A),(B)<(C
)
(8)Z
houetal.
(2012)
[34]
Stress-in
ducedvisceral
hypersensitivity
(SDrat,
m,5-8/group
total94)
(A)M
odel+E
A(2/10
0Hz,0.1m
s,1m
A)
(A)S
T36
1,30min
(B)M
odel
(C)C
ontro
l+Sh
amEA
(ns)
(D)C
ontro
l+EA
(E)M
odel+S
ham
EA(F)M
odel+E
A(G
)Mod
el+E
A+S
AL
(H)M
odel+E
A+N
AL
(I)M
odel+E
A+N
AL
methiod
ide
(C)-(E),(H
)-(J)
ST36
(F)B
L43
1,30min
(1)V
MR
(2)A
WR
(3)D
istentio
npressure
threshold
With
ingrou
p(1),(2)(B):increased
(vs
baselin
e)(3)(B):decreased
(vs
baselin
e)Be
tweengrou
ps(1)(A)<(E),(G
)<(I)(40
,60,80m
mHg)
(2)(A),(C
)<(E)
(D)<(E)(60,80m
mHg)
(G)<(H
)
(9) W
engetal.
(2015)
[39]
Visceralhypersensitivity
+CRD
(SDrat,m,
8/grou
p)
(A)M
odel+E
A(2/10
0Hz,2m
A)
(A)S
T25,37
7,20min
(B)C
ontro
l(C
)Mod
el-
(1)A
WR
(2)P
2X3receptor
incolonic,DRG
,spinalcord,
PFC,
ACC
Betweengrou
ps(1),(2)(A),(B)<(C
)
(10)
Qietal.
(2016)
[41]
Visceral
hypersensitivity
+CRD
(SDrat,m,various/group
total184)
(A)M
odel+E
A(2Hz,1-3
mA)
(B)M
odel+E
A(100Hz,1-3
mA)
(C)M
odel+E
A(2/10
0Hz,1-3
mA)
(A)-(F)S
T36,37
1,10min
(D)M
odel+E
A(2Hz,
1-3mA)+NAL
(E)M
odel+E
A(100Hz,
1-3mA)+NAL
(F)M
odel+E
A(2/10
0Hz,
1-3mA)+NAL
(G)M
odel+
sham
EA(ns)
(H)C
ontro
l
(D)-(G
)ST3
6,37
1,10min
(1)A
WR
(2)A
ctivity
ofrectus
abdo
minis
With
ingrou
p(1),(2)(A)-(C
),(E),(F):
increasedaft
erCR
D,
decreasedaft
ertre
atment
(D),(G
):increasedaft
erCR
D
Evidence-Based Complementary and Alternative Medicine 9
Table3:Con
tinued.
Author
(year)
Mod
el(animal,gender,nu
mber)
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
acup
oints
number,du
ratio
nCon
trol
acup
oints
number,du
ratio
n
(11)Liuetal.
(2017)
[42]
Visceralhypersensitivity
(SDrat,m,8/group
)(A
)Mod
el+E
A(5/25H
z,1m
A)
(A)S
T36,37
4,30min
(B)C
ontro
l(C
)Mod
el(D
)Mod
el+sham
EA(ns)
(C)S
T36,37
4,30min
(1)A
WR
(2)N
R2Bin
spinalcord
Betweengrou
ps(1)(A)<(C
)(2)(A),(B)<(C
),(D
)
(12)
Zhou
etal.
(2017)
[43]
Visceralhypersensitivity
+restraint
stress(SD
rat,
m,16/8)
(a),(b)M
odel+E
A(100Hz,1m
A)
(a),(b)S
T36
(a)1,90m
in(b)1,30m
in
(C)C
ontro
l(d)M
odel
(e)M
odel+
sham
EA(ns)
(f)M
odel+
prop
rano
lol
(g)
Mod
el+p
hentolam
ine
(h)M
odel+S
AL
(d)S
T36
1,30min
(1)A
ctivity
ofacromiotrapezius
(2)E
CG
With
ingrou
p(2)(d):LF/HFincreased
after
restraintstre
ssBe
tweengrou
ps(1)d
uringgastr
icdiste
ntion:
(C),(a),
(b)<(d);(f),(g)<(h)
(2)L
F/HF,LF
:(a)<(d)
Group
writtenin
lowercaselette
rs(e.g.,(
a),(b),and
(c)):differenttreatmentsin
thesam
epop
ulation,un
lessstated
otherw
ise.G
roup
writtenin
capitalletters(e.g.,(
A),(B),and(C
)):differenttreatmentsin
different
popu
latio
n.AC
C:anterio
rcingulatec
ortex;AW
R:abdo
minalwith
draw
alreflex;BL
:Bladd
erMeridian;CR
D:colorectaldistentio
n;DRG
:dorsalroo
tganglion;EA
:electro-acupu
ncture;ECG
:Electrocardiography
;f:fem
ale;HF:
high
frequ
ency
heartratev
ariability;LF
:low
frequ
ency
heartratev
ariability;m:m
ale;mA:m
illiampere;m
in:m
inutes;m
s:millise
cond
s;NR2
B:N-m
ethyl-D
-aspartatereceptor
subu
nitN
R2B;
NAL:
naloxone;n
s:no
tstim
ulated;PFC
:prefro
ntalcortex;RVM:rostralventromediamedulla;SAL:salin
e;SD
:Sprague
Daw
ley;ST
:StomachMeridian;VMR:
visceralmotor
respon
se(reflex);5-HT:
5-hydroxytryptam
ine(serotonin).
10 Evidence-Based Complementary and Alternative Medicine
Table4:Visceralhypersensitivity
mod
elsinanim
alstu
dies
(other
mod
els).
Author
(year)
Mod
el(animal,gender,nu
mber)
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
Acup
oints
number,du
ratio
nCon
trol
Acup
oints
number,du
ratio
n
(1)D
uetal.
(1976)[52]
Splanchn
icnerve
stim
ulation(cat,-,-)
(A)M
odel+E
A(25/70/10
0Hz)
(A)G
B31,34,
LI11,T
E5-
--
(1)V
SRWith
ingrou
p(1)(A):inhibited
(2)Z
hang
etal.
(1989)[53]
Splanchn
icnerve
stim
ulation(cat,-,total
35)
(A)M
odel+E
A(5Hz)
(A)P
C61,3
-5min
(B)M
odel+M
orph
ine
(C)M
odel+E
A+N
AL
(C)P
C61,3-5m
in(1)C
-CEP
s(2)A
-CEP
s
With
ingrou
p(1)(A),(B):redu
ced
amplitu
des
(2)(A),(B):redu
ced
amplitu
deof
late
compo
nent
(3)G
uoxi(19
91)
[54]
Splanchn
icnerve
stim
ulation(cat,m
,total
219)
(A)M
odel+E
A(A
)ST3
6-
--
(1)E
lectric
alactiv
ities
inthalam
us
With
ingrou
p(1)(A):inhibitedin
45ou
tof4
8neuron
s
(4)S
huetal.
(1994)[48]
Splanchn
icnerve
stim
ulation(W
istar
rat,
m,3/4/4)
(A)M
odel+E
A(A
)ST3
6,SP
6-
(B)C
ontro
l(C
)Mod
el-
(1)P
ainthreshold
(2)G
lucose
metabolic
rate
With
ingrou
p(1)(A):increase
after
treatment
Betweengrou
ps(2)(A)<(C
):TD
H,LC,
ventralPAG
,CPC
,HL,
Hippo
,CP,NRD
,NCS
,TP
V,AC
C,accumbens,
NSL,SC
(C)<(A
):LD
H,N
RM,
NRG
,PAG
(B)<(C
):NRM
,PGL,
LC,N
RG,H
A,C
CGM
(5)C
aietal.
(1994)[57]
Splanchn
icnerve
stim
ulation(rabbit,m/f,
8/4/6/6/7/9/6/6)
(A)M
odel+E
A(25H
z)+S
AL
(A)E
X-B2
(T12,L1,L
2)1,30min
(B)M
odel+S
AL
(C)M
odel+MCP
(D)M
odel+E
A(25H
z)+M
CP(E)M
odel+E
A+M
CP+S
AL
(F)M
odel+E
A+M
CP+A
PO(G
)Mod
el+E
A+M
CP+S
KF38393
(H)
Mod
el+E
A+M
CP+L
Y171555
(D)-(H
)EX-
B21,30min
(1)P
ainthreshold
(2) D
Ain
CSF
(3)D
OPA
Cin
CSF
(4)H
VAin
CSF
With
ingrou
p(1)(A),(C
),(D
),(F):
elevatedcomparedto
baselin
e(4)(A),(C
):ele
vated
comparedto
baselin
eBe
tweengrou
ps(1)(A),(C
)<(D
);(B)<(C
);(F),(G
),(H
)<(E)
(4)(A),(C)>(B)
Evidence-Based Complementary and Alternative Medicine 11
Table4:Con
tinued.
Author
(year)
Mod
el(animal,gender,nu
mber)
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
Acup
oints
number,du
ratio
nCon
trol
Acup
oints
number,du
ratio
n
(6)K
won
etal.
(2001)[56]
Aceticacid
injection(ICR
mice,m,10-20/group
)
(A)M
odel+B
V(B)
Mod
el+BV
+NAL
(C)M
odel+B
V+Y
o
(A)C
V12
1,-
(D)M
odel+B
V(E)M
odel+S
AL
(D)n
on-acupo
int
1,-
(1)A
bdom
inalstretches
(2)c-Fos
inspinalcord,
NTS
Betweengrou
ps(1)(A),(D
)<(E)
(2)(A)<(E)
(7)Y
uetal.
(2008)
[55]
Aceticacid
injection
(mice,m/f,
12/group
)
(A)W
TMod
el+MA
(B)C
onnexin43
gene
knockout
HT
Mod
el+MA
(A),(B)
CV12,
ST36
1,30min
(C)W
Tcontrol
(D)H
Tcontrol
(E)W
Tmod
el(F)H
Tmod
el
- -(1)c-Fos
inthes
pinal
dorsalho
rnBe
tweengrou
ps(1)(A)<(E),(A
)<(B)
(8)Y
uetal.
(2008)
[22]
Aceticacid
injection
(mice,m/f,
18/group
)
(A)M
odel+
WTMA
(B)C
onnexin43
gene
knockout
HT
++Mod
el+M
A
(A),(B)
CV12,
ST36
1,30min
(C)W
Tcontrol
(D)H
Tcontrol
(E)W
Tmod
el(F)H
Tmod
el
- -
(1)L
atency
ofwrithing
respon
se(2)N
umbero
fwrithing
respon
se(3)𝛽
-end
orph
inin
hypo
thalam
us(4)P
lasm
aPGE 2
Betweengrou
ps(1),(3)(A)>(E),(A
)>(B)
(2),(4)(A)<(E),(A
)<(B)
(9)L
iuetal.
(2010)
[23]
Aceticacid
injection(SD
rat,m/f,
6/grou
p)
(A)M
odel+E
A(2/20H
z)(B)
Mod
el+EA
+Snake
veno
m(C
)Mod
al+E
A+S
AL
(A)-(C
)ST2
1,20
min
(D)C
ontro
l(E)M
odel
(F)M
odel+E
A+ION
transection
(F)S
T21,20
min
(1)A
bdom
inalmuscular
contractions
(2)c-Fos
expressio
nin
theN
TS(3)c-Fos
expressio
nin
theP
TN
Betweengrou
ps(1),(2)(A),(E)>(D
);(A
),(B),(C
)<(E),(A
)<(F)
(3)(A),(B),(C
)>(E),
(A),(B),(C
)>(F)
(10)
Liuetal.
(2011)[31]
Aceticacid
injection(SD
rat,-,-)
(A)M
odel+E
A(2/20H
z,1.0
mA)
(B)M
odel+E
A(2/20H
z,2.0m
A)
(C)M
odel+EA
(2/20H
z,4.5m
A)
(D)E
A(2/20H
z)(E)-(G
)Mod
el+E
A(2/20H
z)
(A)-(E)S
T2(F)G
B14
(G)S
T61,20min
(H)C
ontro
l(I)M
odel
(J)M
odel+
Sham
EA(ns)
(K)M
odel+E
A(2/20H
z)
(J)S
T2(K
)non
-acupo
int
1,20min
(1)c-Fos
(2)A
bdom
inal
contractions
With
ingrou
p(1)(D):in
theN
TS,
CPTN
,PTN
,postre
ma,
DMNof
thev
agus,R
F(blocked
byinfraorbita
lnerves
transaction
pretreatmentinPT
N)
(1)(B),(C)
,(E),(G),(K
):inhibitedin
NTS
(1)(B)-(E),(G),(K
):increasedin
PTN
(1),(2)(E):infraorbital
nerves
transactionand
capsaicinpretreatment
inhibitedthee
ffectof
EAon
redu
ced(1)a
nd(2)
Betweengrou
ps(2)(D),(E),(G
),(H
),(K
)<(I)
(B),(C
)<(A
),(I),(K
)
12 Evidence-Based Complementary and Alternative Medicine
Table4:Con
tinued.
Author
(year)
Mod
el(animal,gender,nu
mber)
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
Acup
oints
number,du
ratio
nCon
trol
Acup
oints
number,du
ratio
n
(11)Gon
getal.
(1992)[50]
Antim
onium
potassium
tartrateinjection(W
istar
rat,m/f,
15/10
/7/-
/12/8/9/8/6/6/10
/8/15
/15)
(A)M
odel+E
A(45/12.5Hz)
(B)M
odel+E
A(45/12.5Hz)
+electric
alstim
ulationof
PVN
GV26,C
V24
1,20min
(C)C
ontro
l(D
)Mod
el(E)M
odel+S
ham
EA(ns)
(F)M
odel+E
A+sham
stim
ulationof
PVN
(G)M
odel+
EA+lesionof
PVN
(H)M
odel+E
A+sham
lesio
nof
PVN
(I)M
odel+E
A+v
asop
ressin
antagonist
(J)M
odel+
EA+S
AL
(K)M
odel+E
A+v
asop
ressin
antiserum
(L)M
odel+E
A+n
ormal
serum
(M)M
odel+E
A+v
asop
ressin
antagonist
(N)M
odel+E
A+S
AL
(E)-(N
)GV26,
CV24
1,20min
(1)W
rithing
respon
se
Betweengrou
ps(1)(A)<(E),(B)<(F),
(G)>(H
),(I)>(J),
(K)>(L)
(12)
Xuetal.
(2010)
[59]
Form
alin
injection(SD
rat,m,8/group
)
(A)E
A(20H
z,∼1m
A)
(B)M
odel+E
A(20H
z,∼1m
A)
(A),(B)E
X-B2
(L3,6)
1,20min
(C)C
ontro
l(D
)Mod
el-
(1)V
isceralpain
behavior
(2)p
38in
colon,
spinal
dorsalho
rn(3)c-Fos
incolon,
spinal
dorsalho
rn(4)P
lasm
a𝛽-end
orph
in(5)S
Pin
colon
Betweengrou
ps(1)(B)<(D
)(2),(3),(5)(B),(C)<(D
)(4)(C)<(D
)<(B)
(13)
Rong
etal.
(2005)
[44]
CRD(SDrat,m,total67)
(A)M
odel+n
onreceptivefi
eldMA
(2-3Hz)
(B)M
odel+receptiv
efield
MA
(A)S
T36(con
tr)
(B)S
T36(ip
s)1,30s
(C)M
odel
(D) M
odel+n
onreceptive
field
pinch
(E)M
odel+receptivefi
eld
pinch
(F)M
odel+h
otwater
ontail
(non
receptivefi
led)
(G)M
odel+no
nreceptive
field
MA+a
cutefre
ezeo
fspinalcord
(H)M
odel+
acutefreezeo
fspinalcord
(G)S
T36
(con
tralateral)
1,30s
(1)E
lectric
alactiv
ities
ofspinaldo
rsalho
rnWDR
neuron
sofL
1-L3
With
ingrou
ps(1)(A),(D
):decreased
(B),(G
),(H
):increased
Betweengrou
ps(1)(A),(D)<(C
);(A
)<(G
)
Evidence-Based Complementary and Alternative Medicine 13
Table4:Con
tinued.
Author
(year)
Mod
el(animal,gender,nu
mber)
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
Acup
oints
number,du
ratio
nCon
trol
Acup
oints
number,du
ratio
n
(14)R
ongetal.
(2005)
[24]
CRD(SDrat,-,
17/17
/9/15
/9)
(A),(B)M
odel+M
A(2Hz)
(A)S
T36(con
tr)
(B)S
T36(ip
s)1,30s
(C)P
inch
(con
tr)
(D)P
inch
(ips)
(E)M
odel
-(1)E
lectric
alactiv
ities
inspinaldo
rsalho
rn
Betweengrou
ps(1)(A),(C
)<(E)
((A)<(E)effectblocked
after
spinalization)
(15)
Zhangetal.
(200
9)[28]
CRD(SDrat,m,58)
(a),(b)M
odel+E
A(2Hz,1m
A)
(a)S
T36(con
tr)
(b)S
T36(ip
s)1,320s
(c)M
odel
(d)M
odel+E
A(2Hz,1m
A,
0.5m
s)(e)M
odel+E
A(100Hz,1m
A,
0.5m
s)
(c)-(e)centero
freceptivefi
eld
1,320s
(1)E
lectric
alactiv
ities
inthalam
us
Betweengrou
ps(1)(d),(e)<(c)(e)<(d)
(d)<(a),(b)
(16)
Chen
etal.
(2010)
[51]
CRD(W
istar
rat,m,
9/grou
p)
(A)M
odel+E
A(B)M
odel+E
A(C
)Mod
el+E
A(2/15
Hz,2m
A)
(A)S
T36
(B)P
C6(C
)LR3
1,15min
(D)C
ontro
l(E)M
odel+S
ham
EA(non
-acupo
int,2/15Hz,
2mA)
(E)n
on-acupo
int
1,15min
(1)M
AP
(2)H
R(3)H
RVHF
(4)L
F(5)L
F/HF
With
ingrou
p(2)(A),(B)d
ecreased
Betweengrou
ps(1)(A),(B)<(C
),(D),(E)
(4)(A),(B),(C
)<(D
)(5)(A),(B)<(D
)
(17)
Liuetal.
(2014)
[35]
CRD(SDrat,m,62)
(a)-(c)M
odel+E
A(10H
z,2m
A)
(a)S
T36
(b)P
C6(c)A
uricular
acup
oint
(heart)
1,30s
--
(1)E
lectric
alactiv
ities
inNTS
With
ingrou
p(1)(a),(b),(c):reduced
in5-10
neuron
sand
increasedin
2neuron
sam
ong21
excited
neuron
sbyCR
Dreversed
in9-15
neuron
sam
ong24
inhibited
neuron
sbyCR
D
(18)
Yuetal.
(2014)
[36]
CRD(SDrat,m,
10-11/g
roup
)
(a)M
odel+E
A(15H
z,1.5
mA)
(b)M
odel+E
A(15H
z,6m
A)
(c)M
odel+E
A(15H
z,4m
A)
(a)-(c)S
T36,37
2,30s
(d)M
odel
-
(1)E
lectric
alactiv
ities
ofwided
ynam
icrange
neuron
s(2)E
lectric
alactiv
ities
ofSR
Dneuron
s
With
ingrou
p(1)(a),(b):increased
after
treatmentand
CRD
(d):increased
(2)(c),(d):significant
respon
ses
(a),(b):increased
after
CRD
(19)
Lietal.
(2014)
[37]
CRD(SDrat,f,8/7/7/7)
(A)
Mod
el+auricular
EA(25H
z,0.8m
A)
(A)A
uricular
acup
oints
(stomach,sm
all
intestine)
1,30min
(B)C
ontro
l(C
)Mod
el(D
)Mod
el+sham
EA
(D)n
ovagal
innervation
points
1,30min
(1)V
MR
(2)m
RNAof
5-HT1a
receptor
incolon
(3)m
RNAof
5-HT1a
receptor
inraph
enuclei
With
ingrou
p(1)(C)
:increased
Betweengrou
ps(1)(B)<(A
),(C
),(D
)(1),(2)(A)<(C
)(3)(A)<(C
),(D
)
14 Evidence-Based Complementary and Alternative Medicine
Table4:Con
tinued.
Author
(year)
Mod
el(animal,gender,nu
mber)
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
Acup
oints
number,du
ratio
nCon
trol
Acup
oints
number,du
ratio
n
(20)
Yuetal.
(2014)
[47]
CRD(SDrat,m,22)
(a)
preEA+M
odel+E
A(15H
z,1m
A)
(b)
preEA+M
odel+E
A(15H
z,4m
A)
(c)
preEA+M
odel+E
A(15H
z,7m
A)
(d)
preEA+M
odel+E
A(15H
z,10mA)
(a)-(d)S
T36(ip
s)2,30s
-- -
(1)E
lectric
alactiv
ities
ofWDRin
lumbarspinal
cord
With
ingrou
p(1)(a),(b),(c),(d):
increased
(21)Liuetal.
(2015)
[38]
CRD(SDrat,m,8/group
)(A
)Mod
el+E
A(2/10
0Hz)
(A)S
T37
7,20min
(B)C
ontro
l(C
)Mod
el(D
)Mod
el+sham
EA(ns)
(D)S
T37
7,20min
(1)A
WR
(2)C
RHin
colon
(3)C
RHin
spinalcord,
hypo
thalam
us(4)m
RNAof
CRHin
colon,
spinalcord,
hypo
thalam
us
Betweengrou
ps(1)(A),(B)<(C
);(A
)<(D
)(2)(A),(B),(D
)<(C
)(3)(A),(B)<(C
),(D)
(except(A)<(D
)inthe
spinalcord)
(4)(A),(B)<(C
);(B)<(D
)<(C
)(on
lyin
hypo
thalam
us)
(22)
Rong
etal.
(2015)
[40]
CRD(SDrat,m,26)
(a)M
odel+E
A(20H
z)(A
)ST3
6,37
2,30s
(b)M
odel
-(1)D
ischargefrequ
ency
ofVPL
neuron
sin
thalam
us
With
ingrou
p(1)(a):increased
after
CRD
(b):increased
(23)
Iwae
tal.
(2005)
[58]
Rectaldiste
nsion(D
og,f
4,6/grou
p)(A
)Mod
el+E
A(10H
z)(A
)ST3
61,30min
(B)M
odel+E
A(C
)Mod
el+E
A+N
AL
(D)M
odel+E
A+N
AL
methiod
ide
(B)B
L21
(C),(D
)ST3
61,30min
(1)A
rterial
b loo
dpressure
With
ingrou
p(1)(A),(D
):decreased
after
treatment
(24)
Linetal.
(200
9)[45]
Gastricdiste
nsion(SDrat,
m,10/grou
p)
(A)M
odel+E
A(2Hz,1-3
mA)
(B)M
odel+E
A(100Hz,1-3
mA)
(A),(B)
ST36
7,30min
(C)C
ontro
l(D
)Mod
el(E)S
ham
mod
el
- -
(1)P
ainscore
(2)𝛽
-end
orph
inin
hypo
thalam
us(3)S
Pin
hypo
thalam
us
With
ingrou
p(1)(A),(B)d
ecreased
Betweengrou
ps(1)(B)>(A
)>(D
)>(C
),(E)
(2),(3)
(A)>(B)>(D
)>(C
),(E)
Evidence-Based Complementary and Alternative Medicine 15
Table4:Con
tinued.
Author
(year)
Mod
el(animal,gender,nu
mber)
Acup
unctureg
roup
sCon
trolgroup
sOutcomes
Results
Acup
uncture
Acup
oints
number,du
ratio
nCon
trol
Acup
oints
number,du
ratio
n
(25)
Sunetal.
(1991)[49]
Somaticandvisceral
noxiou
sstim
uli(Wistar
rat,m/f,
23/28/-/16)
(A)M
odel+E
A(6v,
8Hz)
(A)S
T36
1,15min
(B)M
odel
(C)M
odel+M
orph
ine
(D)M
odel+M
orph
ine+
NAL
- -
(1)D
ischargeo
fPEN
inVPN
(2)D
ischargeo
fPIN
inVPN
With
ingrou
p(1)(A):redu
ced
(2)(A):enhanced
(26)
Lorenzini
etal.(2010)[30]
Cystitis
(SDrat,m,total
48)
(A)C
ystitis+
PWL
(A)-(F)S
T36,
TE5
Vario
us(B)C
ystitis
-
(1)U
rinarybladder
weight,mucosalerosion,
ulceratio
n,edem
a,petechialh
emorrhages,
thickn
esso
fbladd
erwall
(2)V
isceralpain
behavior
With
ingrou
p(1),(2)(A),(B):
increased
(27)
Yang
etal.
(2010)
[46]
Visceraltractio
n(SDrat,
m,10/grou
p)(A
)Mod
el+LA
(650nm
,10m
W)
(A)S
T36
1,30min
(B)S
ham
mod
el(C
)Mod
el(D
)Mod
el+M
oxa
(D)S
T36
1,30min
(1)P
ainscore
(2)S
ystolic
pressure
(3)A
ChE
(4)S
P(5)L
EK(6)P
ositive
indexof
c-Fo
sprotein
(7)P
ositive
indexof
GFA
P
Betweengrou
ps(1),(3)(A),(B),(D
)<(C
)(2)(A),(B)<(C
)(4)(B)<(A
)<(D
)<(C
)(5)(A)>(B),(C)
,(D)
(6),(7)(B)<(A
),(D)<(C
)
Group
writtenin
lowercaselette
rs(e.g.,(
a),(b),and
(c)):differenttreatmentsin
thesam
epop
ulation,un
lessstated
otherw
ise.G
roup
writtenin
capitalletters(e.g.,(
A),(B),and(C
)):differenttreatmentsin
different
popu
latio
n.AC
C:anterio
rcingu
late
cortex;A
-CEP
s:corticalevoked
potentialsof
A-fib
ers;AC
hE:acetylcho
linesterase;A
PO:apo
morph
ine;AW
R:Ab
dominalwith
draw
alreflex;BL
:Bladd
erMeridian;
BV:b
eeveno
m;C
-CE
Ps:corticalevoked
potentialsof
C-fib
ers;CC
GM:centraliscorpus
geniculatum
medialis;con
tr:con
tralateral;C
P:caud
atep
utam
en;C
PTN:caudalspinaltrig
eminalnu
cleus;C
RD:colorectald
istensio
n;CR
H:
corticotropin-releasingho
rmon
e;CS
F:cerebrospinalfl
uid;
CV:C
onceptionVe
sselMeridian;
DA:d
opam
ine;DMN:d
orsalm
otor
nucle
us;D
OPA
C:do
paceticacid;E
A:electro-acupu
ncture;f:fem
ale;GB:
Gall
BladderM
eridian;
GFA
P:glialfi
brillaryacidicprotein;
GV:
Governing
VesselMeridian;
HA:hypothalamicarcuatus;H
F:high
frequ
ency
heartratevaria
bility;Hippo
:hippo
campu
s;HL:
habenu
laelateralis;H
R:heartrate;HRV
:heartratevaria
bility;HT:
heterozygote;H
VA:hom
ovanillicacid;ION:infraorbitaln
erve;ips:ipsilateral;IT:intrathecalinjection;
L:lumbarv
ertebrae;L
A:laser
acup
uncture;LC
:locus
coeruleus;
LDH:lum
bardo
rsal
horns;LE
K:leu-enkeph
alin;L
F:low
frequ
ency
heartratevaria
bility;
LI:L
arge
Intestine
Meridian;
LR:L
iver
Meridian;
m:m
ale;MA:m
anuala
cupu
ncture;m
A:m
illiampere;M
AP:
mean
arteria
lpressure;MCP
:metoclopram
ide;min:m
inutes;M
oxa:moxibustio
n;mRN
A:m
essenger
ribon
ucleicacid;m
s:millise
cond
s;NAL:
naloxone;N
CS:n
ucleus
centralis
superio
r;NRD
:nucleus
raph
edo
rsalis;
NRG
:nucleus
retic
ular
gigantocellularis
;NRM
:nucleus
raph
emagnu
s;ns:n
otstimulated;N
SL:nucleus
septallateralis;N
TS:nucleus
tractussolitarii;PAG
:periaqu
eductalgray;PC
:Pericardium
Meridian;
CPC:
centromedian-parafascicula;PE
N:pain-excitatio
nneuron
s;PG
E2:prosta
glandinE2
;PGL:paragigantocellularis
lateralis,PIN
:pain-inhibitory
neuron
s;PT
N:paratrig
eminalnu
cleus;PV
N:paraventricularnu
cleus;
PWL:
pulse
dwavelaser;RF
:reticular
form
ation;
SAL:
salin
e;s:second
s;SC
:som
atosensory
cortex;SD:Sprague
Daw
ley;SP
:sub
stance
P;SR
D:sub
nucle
usretic
ularisdo
rsalis;
ST:StomachMeridian;
T:thoracic
vertebrae;TD
H:tho
racicd
orsalhorns;T
E:TripleEn
ergizerM
eridian;TP
V:thalam
icpo
sterio
rventralis;
VMR:
visceralmotor
respon
se(reflex);VPL
:ventralispo
sterio
rlateralis;
VPN
:ventralpo
sterolateralnucleus;
VSR:
viscerosom
aticreflexdischarges;W
DR:
wided
ynam
icrange;WT:
wild
type;Yo:yohimbine;5-H
T:5-hydroxytryptam
iner
eceptor.
16 Evidence-Based Complementary and Alternative Medicine
3.3.3. Outcomes and Results
(1) Behavioral Outcomes. In the animal studies, the abdominalwithdrawal reflex [25–27, 32–34, 38, 39, 41, 42], abdominalmuscle activities, writhing responses in the abdomen and leg,and other pain-related behaviors significantly decreased afteradministering EA [29, 45, 48, 50] (Tables 3–5).
(2) Metabolic Outcomes. Liu et al. found that EA treatmentapplied at the ST25 and ST37 points reduced the concen-trations of 5-hydroxytryptamine (5-HT) when compared tothe concentrations observed in the no-treatment visceralhypersensitivity group [27]. Xu et al. also showed increased𝛽-endorphin levels in the EA treatment group compared toin the no-treatment formalin injectionmodel [59] (Figure 3).
(3) Gut. The concentration levels of serotonin-related factors,hormones, neurotransmitters, and other molecular signalingfactors in the colon were observed in the animals before andafter acupuncture. The expression levels of serotonin and c-Fos dropped significantly after EA treatment [26, 29]. Theexpression levels of serotonin transporter (additional wateravoidance stress model) [26], c-Fos [23], p38 [23], substanceP [23, 46], corticotropin-releasing hormone (CRH) [38],P2X3 receptor [39], acetylcholinesterase (AchE) [46], andthe serotonin concentration [27] were significantly loweredafter EA. The expression levels of the serotonin transporter(colorectal irritation model) [26], 5-HT4 receptor [27], andleu-enkephalin [46] significantly increased after EA and LA(Tables 3–5, Figure 3).
(4) Spinal Cord. In the spinal cords of the studied ani-mals, neuronal activities, glucose metabolic rates, hor-mones, serotonin-related factors, and pain-related moleculeswere observed before and after acupuncture. The glucosemetabolic rates were significantly decreased in the thoracicdorsal horns and increased in the lumbar dorsal horns andin the periaqueductal gray matter after EA [48]. In thelumbosacral spinal cord, the expression levels of serotoninand c-Fos decreased significantly after EA compared to aftersham EA [29]. The c-Fos expression levels also decreasedin various regions of the spinal cord after EA [23, 31–33] and MA [55]. The neuronal activity of the dorsal rootganglion significantly decreased after EA [10] and that of thespinal dorsal horn significantly decreased after MA [24]. Theexpression levels of p38 in the spinal dorsal horn [40], CRH[38], P2X3 receptor [39], and the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor [42] decreased furtherafter EA (Tables 3–5, Figure 3).
(5) Brain and Brain Stem. In the animal studies, the glucosemetabolic rates, the levels of serotonin-related neurotrans-mitters, hormones, and neuronal activity along with thelevels ofmolecular signaling associatedwith this activity weremeasured. After EA, the glucose metabolic rates significantlydecreased in many regions, e.g., in the thalamus, anteriorcingulate cortex (ACC), nucleus accumbens, and somatosen-sory cortex, and they increased in the nucleus raphe magnus[48]. A significantly increased thalamic neuronal response tocolorectal distention was found after EA (versus nonacupoint
EA) [28]. CRH concentrations in the hypothalamus weresignificantly decreased after EA [38], and 𝛽-endorphin levelsin the hypothalamus were significantly elevated after MA[22]. 𝛽-endorphin and substance P levels in the hypothala-mus showed significant increases after EA [45]. The P2X3receptor expression levels in the prefrontal cortex (PFC) andin the ACC significantly decreased after EA [39] (Tables 3–5,Figure 3).
4. Discussion
To our knowledge, this is the first study to systematicallyreview the mechanisms behind the effects of acupunctureon visceral pain studied in both humans and animalsthrough the brain-gut axis. In the 46 included studies in ourreview, significant improvements in pain-related behaviorswere consistently reported in both humans and animalsincluded in the acupuncture treatment groups compared tothose included in the sham acupuncture or no-treatmentgroups. Increased secretion of 𝛽-endorphin and decreasedepinephrine, cortisol, and PGE2 levels may be involved inthe acupuncture mechanisms at the systemic level that areresponsible for the modulation of visceral pain. Acupunc-ture treatment reduced c-Fos, substance P, CRH, P2X3,AchE, serotonin, and NMDA receptor expression levels andelevated serotonin receptor/transporter and leu-enkephalinexpression levels in the gut and spinal cord. Studies report-ing on the functional neuronal activity showed that EAincreased the activity of the thalamus more than sham EAduring colorectal distention. The effects of acupuncture wereblocked by spinalization [24], acute freezing of the spinalcord [44], naloxone [10, 41], capsaicin [31], and infraorbitalnerve transection [23, 31, 41], indicating the requirements foracupuncture to have an effect. Moreover, it is conceivablethat the mechanisms underlying the effects of EA may differdepending on the frequency of EA administrations. Qi et al.[41] reported that the administration of naloxone inhibitedthe effects of 2Hz EA but not those of 100Hz or 2/100Hz EA(alternate stimulation at 2Hz and 100Hz frequencies).
4.1. Plasma. Pain commonly causes hyperactivity of thehypothalamic-pituitary-adrenal system resulting in elevatedplasma hormone levels such as those of cortisol, epinephrine,and adrenocorticotropin [60]. In their review, Kotani et al.reported that the increased levels of epinephrine and cor-tisol in plasma after abdominal surgeries were significantlyreduced by MA than by sham acupuncture [19]. Previousstudies have also reported that acupuncture attenuated theepinephrine [61] and cortisol [62, 63] levels in plasma.With regard to how EA normalized the increased low-frequency/high-frequency ratio caused due to stress in thefunctional dyspepsia model [43], the results we have dis-cussed demonstrate themodulatory effects of acupuncture onacute stress caused by visceral pain via sympathetic activityand the hypothalamic-pituitary-adrenal axis.
4.2. Gut. Since visceral pain originates in the gastrointestinaltract and its peripheral regions, changes in the immune andnervous systems and changes in the microbial environment
Evidence-Based Complementary and Alternative Medicine 17Ta
ble5:Summaryof
significantresultsfro
mtheincludedstu
dies.
Outcomes
With
inacup
unctureg
roup
(baseline
vspo
st-tre
atment)
vs.sham
acup
unctureg
roup
vs.notre
atmentg
roup
Behavioral
Hum
anIntake
ofanalgesic
s↓[17,19]
Analgesiceffect↑
[16,18,19]
Animal
Pain
score↓
Pain
threshold↑[45,48]
Pain
threshold↑[32]
Pain
score/behavior↓[46,59]
Pain
threshold↑[29]
Abdo
minalwith
draw
alreflex↓[32,41]
Abdo
minalwith
draw
alreflex↓[34,38]
Abdo
minalwith
draw
alreflex↓[25–27,33,38,39,42]
Abdo
minalmuscle
activ
ity↓[31,56]
Abdo
minalmuscle
activ
ity↓
[10,29,34,37]
Abdo
minalmuscle
activ
ity↓[23,25,43]
Writhing
respon
se↓[50]
Writhing
respon
se↓[22]
Metabolic
Hum
an𝛽-end
orph
in↑[20]
Adrenalh
ormon
es↓[19
]
Animal
𝛽-end
orph
in↑[59]
Serotonin/5-HT3receptor↓[27]
Gut
Animal
c-Fo
s↓[29]
Serotonin↓5-HT4
receptor↑[27]
Serotonintransporter↑
[26]
c-Fo
s↓p38↓[59]
AchE↓Leu-enkeph
alin↑[46]
SubstanceP↓[46,59]
CRH↓[38]
P2X3↓[39]
Spinalcord
Animal
Neuralactivity
inwided
ynam
icrange
neuron
s↑[44,47]/↓[44]
Serotoninandc-Fo
sinsuperficialdo
rsal
horn↓[29]
Metabolicrateof
glucoseinthoracicdo
rsalho
rns↓
/lumbard
orsal
horns↑
[48]
Neuralactivity
inwided
ynam
icrangen
eurons↓[44]
Neuralactivity
inspinaldo
rsalho
rn↓[24]
Actio
npo
tentialindo
rsalroot
gang
lion↓[10]
c-Fo
sinspinaldo
rsalho
rn↓[55]
P38in
spinaldo
rsalho
rn↓[59]
NR2
Bin
spinaldo
rsalho
rn,centralcanalregion↓[42]
CRH↓[38]
P2X3↓[39]
Brain/brainste
m
Hum
anPerig
enualcingu
late/prefro
ntalcortex,
tempo
rallob
es,insula,somatosensory
cortex↑[15]
Thalam
us,insula↑
[15]
Animal
Neuralactivity
insubn
ucleus
retic
ularis
dorsalis↑[36]
Disc
hargefrequ
ency
ofthalam
us↑[40]
Activ
ityof
thalam
us↓[54]
Pain
inhibitory
neuron
s↑,
pain
excitatio
nneuron
s↓in
ventral
poste
rolateraln
ucleus
(thalam
us)[49]
Hom
ovanillicacid
inthefou
rthventric
le↑[57]
Neuronalrespo
nsetocolorectal
diste
ntionin
thalam
us↑[28]
Serotoninandc-Fo
sindo
rsalraph
enu
cleus↓[29]
Glucose
metabolicratein
ventralp
eriaqu
eductalgray,nu
cleus
centralis
superio
r↓/p
eriaqu
eductalgray,gigantocellularreticular
nucle
us↑[48]
c-Fo
s,glialfi
brillaryacidicproteinin
medulla↓[46]
c-Fo
sinnu
cleus
tractussolitarii↓[56]
inparatrigem
inalnu
cleus↑[23]
NMDAreceptor
1inrostralventro
medialm
edulla↓[32]
CRHin
hypo
thalam
us↓[38]
P2X3
receptor
inprefrontalandanterio
rcingu
latedcortex↓[39]
Hom
ovanillicacid
inthefou
rthventric
le↑[57]
𝛽-end
orph
inin
hypo
thalam
us↑[22,45]
SubstanceP
inhypo
thalam
us↑[45]
AChE
:acetylcho
linesterase;C
RH:c
orticotropin-releasingho
rmon
e;NMDA:N
-methyl-D
-aspartate;N
R2B:
N-m
ethyl-D
-aspartate
receptor
subu
nitNR2
B;5-HT:
5-hydroxytryptam
inereceptor;P
2X3:
P2X
purin
oceptor3
.
18 Evidence-Based Complementary and Alternative Medicine
of the gut have been investigated. 𝛽-endorphin is an endoge-nous opioid neuropeptide that has an analgesic effect [64],and PGE2 is a hormone-like substance that participates in awide range of bodily functions such as muscle activity, bloodpressure control, pain sensation, and inflammation [65].Neu-rotransmitter substance P, the levels of which decreased afteracupuncture [23, 46], is also involved in inflammation andplays an important role in the mechanisms of acupuncturerelated to pain modulation [66]. Serotonin, another impor-tant neurotransmitter in the CNS and gastrointestinal tract,regulates various functions of the digestive tract. Serotoninand its receptors are extensively distributed in the myentericnerve plexus and participate in the regulation of abnormalsymptoms in the GI tract [67, 68]. It has been reported thatthe levels of serotonin and the activities of various typesof its receptors are found to be increased in the intestinalmucosa of visceral pain patients [69]. Serotonin induces andmaintains visceral hyperactivity bymodulating the activationof the transient receptor potential vanilloid 1 (TRPV1) [70];thus, serotonin receptor agonists or antagonists have beeninvestigated for the treatment of IBS patients [71, 72]. In ourreview, three studies reported that serotonin levels were lowerin the EA groups compared to in the sham EA [29] or notreatment groups [27] or in the model groups [26] while 5-HT4 receptor and serotonin transporter levels significantlyincreased after EA treatment in visceral pain models [26, 27]and decreased after EA treatment in visceral pain groupsthat received additional stress conditions [26]. These resultssuggest that changes in neuropeptide concentrations mayvary depending on the type of visceral pain model and thestress levels and that acupuncture has bidirectional effects ondiverse systems in order to modulate pain.
4.3. Spinal Cord. The spinal cord is the first region in whichincoming pain signals are transmitted to the central nerves.The spinal cord receives sensory information from the wholebody and transmits this information to several regions of thebrain that are responsible for processing pain [73]. In thisreview, the studies reported that the action potential, c-Fos,serotonin, p38, andNMDAreceptor levels in the spinal dorsalhorn were all significantly decreased after EA [10, 29]. C-Fosis commonly used as a marker to measure neuronal activity[74]; thus, increased c-Fos activation in response to the spinalcord signals represents the excitement of the CNS, similar tothe effects of an increased action potential. Serotonin, p38,and NMDA receptors are involved in the development ofvisceral pain [75] and the central sensitization of visceral pain[76]. In addition, the effects of acupuncture were inhibitedby spinalization [24]. These results indicate that the spinalcord plays a critical role in the analgesic mechanism ofacupuncture for visceral pain. However, conflicting resultsamong electrical or chemical measurements associated withvarious nuclei hinder the development of an integrativeunderstanding.
4.4. Brain. A set of brain regions, collectively called the“visceral pain network,” are the core of the perception andmodulation of internal and external stimuli in the gut [77,
78]. An fMRI study found that the activities of the thala-mus and insula significantly increased during EA treatmentcompared to during sham EA stimulation when the partici-pants underwent visceral distention [15]. Complementary tofMRI measurements in humans, which could not distinguishbetween the excitatory and inhibitory neurons, Sun et al.[49] reported that EA significantly reduced the discharge ofpain excitation neurons and enhanced the discharge of paininhibition neurons in the thalamus of rats. This bidirectionalinfluence of acupuncture (to inhibit or enhance neuronalactivity) might have led to the inconsistent results in theevaluations of the thalamic activity during/after acupunc-ture in the animal studies. In other visceral pain networkregions, P2X3 receptor activity was decreased more in thePFC and ACC in the EA group (versus no-treatment IBSmodel group) during colorectal distention [39].The thalamusreceives signals from its periphery and relays them to thehypothalamus, insula, PFC, and motor and somatosensorycortex—the so-called visceral pain network [79–81]. Theinsula integrates sensory information received from visceraland motor activities with inputs from the limbic system[77, 80]. The thalamus is mainly associated with the first-order processing of sensory information, whereas the PFC,insula, and ACC tend to be associated with the higher-orderprocessing of cognitive evaluation, attention, sensory-motorintegration, and affective responses [77]. This observationimplies that acupuncture treatment influences higher-levelcortical activity along with the primary visceral sensoryprocessing regions.
4.5. Quality Assessment of the Included Studies. We onlyassessed the quality of the human studies and found thatonly three studies were classified as having low overall risksof bias while two studies were considered as having highrisks of bias. A few assessment tools have been developed forassessing the quality of animal studies, but they are not widelyaccepted nor validated in the field yet. Moreover, since mostof the animal studies included in our review did not reporton having employed ways to minimize the risk of bias, suchas the blinding of the outcome assessor or randomizationmethods, we could only assume that they were at high risksof bias.
It is also important to assess the reporting quality of theacupuncture interventions.There are well-known guidelines,the STRICTA guidelines (STandards for Reporting Interven-tions in Clinical Trials of Acupuncture [82, 83]), for clinicalstudies that use acupuncture treatment. However, there areno such guidelines that have been designed specifically forreporting acupuncture interventions in animal studies. Forthese reasons, we evaluated the quality of reporting onacupuncture interventions according to the STRICTA guide-lines in a separate paper [84]. To improve our understand-ing of the underlying mechanisms of acupuncture that areinvolved in the treatment of visceral pain, studies conductedaccording to well-validated guidelines with detailed reportson the acupuncture intervention employed are warranted.
4.6. Summary. Based on these results, we found thatacupuncture induces analgesic effects on visceral pain via
Evidence-Based Complementary and Alternative Medicine 19
multiple pathways from the peripheral organs (gut) to theCNS (brain). Visceral organs are where visceral pain occurs,and acupuncture directly regulates visceral pain by reducingthe levels of intrinsic inflammatory biomarkers and increas-ing the levels of serotonin and endogenous opioid neuro-transmitters. The neural signals induced by acupuncture arealso transmitted to the brain through the spinal cord, and itattenuates the peripheral neural activity and concentrationsof the inflammatory-biomarkers such as p38, P2X3, andNR2B in the spinal cord. In the brain, acupuncture attenuatesthe levels of neural activity and pain excitation neurons inthe thalamus and reduces stress-related hormone levels in thehypothalamus, which suggests that the neural and hormonalchanges in the thalamus and hypothalamus are involved inthe pain modulatory effects of acupuncture on visceral pain.Moreover, acupuncture induces an increase in the levels of 𝛽-endorphin and pain inhibitory neurons that are also relatedto pain inhibition.
With this review, we were able to present the broadoutline of the acupuncture signal-transduction system fromthe gut to the CNS, but the acupuncture signaling pathwaysfrom the spinal cord to the intestine or the gut-brain signal-transduction system are still unclear. Further experimentalstudies are needed to elucidate the entire signaling mech-anism of acupuncture from the peripheral to the centralorgans.
5. Conclusion
This review summarizes the findings from previous studiesassociated with the neural and chemical changes that takeplace through the brain-gut axis in both humans and animalsin order to reveal the underlying mechanisms behind theeffects of acupuncture treatment on visceral pain. The resultsof this review demonstrated significant improvements invisceral pain following acupuncture treatments. However,achieving an integrative understanding of the mechanism ofacupuncture on visceral pain remains a long-term endeavor.High heterogeneity among the included studies (variousvisceral pain conditions and models along with diverseoutcome measures and heterogeneous results) and the lackof detailed descriptions outlining the treatment methods alsoraise concerns.
In future studies, the thalamus and the brain-gut axiscould be considered as targets or markers of the visceral painthat is modulated by acupuncture. Furthermore, studies onchanges in the levels of neurotransmitters or neuropeptides inthe gut and the brain may improve our knowledge of visceralpain modulation by acupuncture treatment.
Conflicts of Interest
The authors declared no conflicts of interest.
Authors’ Contributions
This review was conceived and designed by Ji-Yeun Parkand In-Seon Lee. Ji-Yeun Park and In-Seon Lee developed
the search strategy, and In-Seon Lee conducted the databasesearch. Ji-Yeun Park, In-Seon Lee, and Soyeon Cheonassessed studies for inclusion and extracted and analyzedthe data. Ji-Yeun Park, In-Seon Lee, and Soyeon Cheonprepared the manuscript draft. All the authors approved thefinal version of the manuscript for publication. In-Seon Leeis currently supported by the Intramural Research Programof the National Center for Complementary and IntegrativeHealth, National Institutes of Health.
Acknowledgments
This work was supported only by the Daejeon UniversityResearch Grants (2016).
Supplementary Materials
Two supplementary tables reporting the risk of bias ofincluded clinical studies regarding the quality of the includedstudies. We assessed the risk of bias with RoB 2.0 tool forrandomized controlled trials (n=6, supplementary Table 1)and ROBINS-I tool for non-randomized clinical trial (n=1,supplementary Table 2). (Supplementary Materials)
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