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JTCM
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www. journaltcm. com October 15, 2019
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Volume 39
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Issue 5
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Online Submissions: http://ww w.journaltcm.com J Tradit Chin Med 2019 October 15; 39(5): 740-749
info@journaltcm.com ISSN 0255-2922
© 2019 JTCM. All rights reserved.
REVIEW
Mechanism of electroacupuncture on inflammatory pain: neural-im-
mune-endocrine interactions
Li Yuan, Yang Mingxiao, Wu Fan, Cheng Ke, Chen Haiyong, Shen Xueyong, Lao Lixing
aa
Li Yuan, Wu Fan, Cheng Ke, Shen Xueyong, Lao Lixing,
School of Acupuncture Moxibustion and Tuina, Shanghai
University of Traditional Chinese Medicine, Shanghai
201203, China
Yang Mingxiao, Chen Haiyong, Lao Lixing, School of Chi-
nese Medicine, The University of Hong Kong, Hong Kong,
China
Supported by the National Natural Science Foundation of
China (No. 81320108028, Efficacy and Neurobiological
Mechanisms of Traditional Moxibustion-based Laser Moxi-
bustion with Specific Wavelength on Inflammatory Pain),
the Three-Year Development Plan Project for Traditional Chi-
nese Medicine of Shanghai Municipal Health Commission
[ZY (2018-2020)-CCCX-2001-05], the National Basic Research
Program of China (973 Program, No. 2015CB554505), Shang-
hai Key Laboratory of acupuncture mechanism and acu-
point function (No. 14DZ2260500), Shanghai University of
Traditional Chinese Medicine budget research project
(No.18LK010), and Li Yuan's postgraduate innovation ability
project (No. A1-N192050102040105)
Correspondence to: Prof. Shen Xueyong, School of Acu-
puncture Moxibustion and Tuina, Shanghai University of Tra-
ditional Chinese Medicine, Shanghai 201203, China. snow-
ysh@hotmail.com; Prof. Lao Lixing, School of Chinese Medi-
cine, The University of Hong Kong, Hong Kong, China;
School of Acupuncture Moxibustion and Tuina, Shanghai
University of Traditional Chinese Medicine, Shanghai
201203, China. lxlao1@hku.hk
Telephone: +86-21-51322178;+852-39176476
Accepted: January 9, 2019
Abstract
Nociceptive signals are transmitted by peripheral
afferents to the central nervous system under pain
condition, a process that involves various neu-
rotransmitters and pathways. Electroacupuncture
(EA) has been widely used as a pain management
technique in clinical practice. Emerging studies
have shown that EA can inhibit the induction and
transmission of pain signals and, consequently, me-
diate anti-nociceptive and anti-inflammatory ef-
fects by rebalancing the neural-immune-endocrine
interactions. This review summarizes the neural-im-
mune-endocrine circuit including peripheral affer-
ent and central efferent, contributing to EA-in-
duced neuroimmune and neuroendocrine modula-
tion in inflammatory pain models. The peripheral
afferent circuit includes crosstalk among immune
cells, inflammatory cytokines, peripheral nocicep-
tors. In central efferent primarily involves the neuro-
inflammatory interactions between spinal nocicep-
tive neurons and glial cells. Furthermore, the hypo-
thalamic-pituitary-adrenal axis, sympathetic and va-
gal nervous may serve as an essential pathway in-
volved in the mechanism of acupuncture-mediated
analgesia within the interactions of the central, im-
mune and endocrine systems. Overall, this review
focuses on the interactions of neural-immune-en-
docrine in inflammatory pain, which may be under-
lying the mechanism of EA-induced anti-inflamma-
tory and antinociceptive effect.
© 2019 JTCM. All rights reserved.
Keywords: Electroacupuncture; Analgesia; Inflam-
matory pain; Neural-immune-endocrine interac-
tions; Review
INTRODUCTION
Inflammatory pain, which is caused by the activation
of peripheral nociceptors in the nervous system by nox-
ious chemicals and mechanical or thermal stimuli, is
not only a warning signal for local tissue damage and
nerve injury but can also be an indicator of systemic ill-
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ness.1Physiologically, nociceptive signals that are medi-
ated by central neural circuits lead to the perception of
pain. Pain perceived by the brain can have regulatory
effects that maintain the homeostasis of the immune,
autonomic and endocrine systems. The dysregulation
of these bidirectional signaling pathways results in
chronic inflammatory pain.2,3 During this process, pe-
ripheral tissue damage induces inflammatory responses
by triggering immune cells to release a series of inflam-
matory mediators. These mediators bind with recep-
tors expressed on nociceptive neurons, causing the neu-
rons to depolarize and generate action potentials,
which further transmit the nociceptive signals to the
spinal dorsal horn and the brain, contributing to the in-
duction and maintenance of perceived pain.4More-
over, peripheral inflammatory mediators, such as in-
flammatory cytokines, can be activated by vagal and
sympathetic nerves, which can aggravate pain and in-
flammation through cross-talk between the neuroim-
mune and neuroendocrine systems.3, 5
Electroacupuncture (EA), as a complementary and al-
ternative therapy, has been shown to have substantial
beneficial effects on pain relieving.6Though the mecha-
nisms of action underlying these effects remain to be
elucidated, EA may exert a comprehensive modulatory
effect on inflammatory pain, affecting the entire ner-
vous system [including the peripheral nervous system
(PNS) and the central nervous system (CNS)], the im-
mune system, and the endocrine system. Due to the
complexity of pain, a more comprehensive elucidate
the mechanisms underlying the EA-mediated regula-
tion of inflammatory pain within the interactions of
central, immune and endocrine systems is of great clini-
cal significance. This review summarizes the recent
progress towards understanding this process and pro-
poses a mechanism for the multisystem regulatory ef-
fects of EA during inflammatory pain.
Anatomical structure of acupuncture points
Acupoints can be sensed and transduced by a variety of
stimulation types, such as mechanical stimulation me-
diated by acupuncture needle, thermal stimulation by
moxibustion, electrical stimulation by EA, and radia-
tion by laser beams. The ability of acupoints to trans-
duce stimuli plays an important role in acupunc-
ture-mediated effects on pain.7,8 According to classical
acupuncture theories, disorders of the visceral organs
can be manifested at specific points, either on or under-
neath the skin surface, which is how acupoints have his-
torically been defined.9Despite considerable efforts to
better understand the anatomy and physiology of acu-
puncture points and meridians, the definitions and
characterizations of these structures remain inconclu-
sive. Early morphology studies analyzed the anatomical
structures surrounding acupoints, suggesting that ner-
vous system components, blood vessels, and musculosk-
eletal tissues represent important constituents of acu-
points.10-12 The anatomical structures surrounding acu-
puncture points transmit the neuroimmune and neuro-
inflammation signals induced by stimulation with EA
or manual acupuncture.13 Recent studies have shown
that mast cells (MCs), which are important compo-
nents of the immune system, could be potential effec-
tor cells at acupoints.14,15 EA stimulation at acupoints
has been shown to result in MC degranulation and af-
ferent nerve excitation,16 which is closely related to acu-
point sensitization17 and EA-mediated analgesia.15 Fol-
lowing acupuncture stimulation, MCs not only initiate
a neuroimmune response by releasing inflammatory
mediators but also play a crucial role in the cross-talk
among the circulatory, nervous and immune networks
at acupoints.16,18 A recent study showed that transcuta-
neous electrical acupoint stimulation at Binao (LI 14)
acupoint induced sensory nerve fibers to express calci-
tonin gene-related peptide and substance P, which bind
with the neurokinin 1 receptor on MCs. This interac-
tion resulted in the degranulation of MCs, releasing
5-hydroxytryptamine (5-HT), and thus producing an-
algesic effect similar to that of EA.19 Other studies have
also demonstrated that electrical stimulation at the Zu-
sanli (ST 36) acupoint activates the immune system by
regulating the production of immune cytokines, such
as interferon gamma (IFN-γ), interleukin-2 (IL-2) and
interleukin-17 (IL-17), and the differentiation and acti-
vation of splenic T cells.20
Peripheral afferent neuroimmune and
neuroendocrine modulation
Peripheral nociceptive afferent fibers include Aδ- and
C-fibers, which have peripheral axonal branches at no-
ciceptor terminals. These fibers are found in the dorsal
root ganglion (DRG), the trigeminal ganglion, the no-
dose ganglion of the vagal nerve, and the central axonal
branch, all of which form synaptic connections with
neurons in the spinal dorsal horn (SDH).4The nocicep-
tive signals induced by chemical, mechanical, or ther-
mal stimuli leading to changes in the responsiveness of
peripheral nociceptors and peripheral sensitization in-
cluding hyperalgesia and allodynic.
The neural mechanism underlying acupuncture/EA-
mediated analgesia has been addressed previously and
includes a wide spectrum of modulating effects mediat-
ed by peripheral afferent pathway, transmitters and
modulators.10,21 A large number of studies have ex-
plored the distinct roles played by the non-nociceptive
large afferent fiber (Aβ-fiber) and the nociceptive small
afferent fibers (Aδ- and C-fibers), which are found in
the peripheral neural pathways, during EA-induced an-
ti-nociceptive signaling.22 The transient receptor poten-
tial vanilloid receptors 1 (TRPV1) and 4 (TRPV4),
and the acid-sensing ion channel 3 (ASIC3) are mecha-
nosensitive channels associated with the release of ade-
nosine triphosphate (ATP) in various local tissues.23-25
Structurally, they are membrane channel proteins that
become permeable to cations, such as sodium and calci-
um, following mechanical stimulation. ASIC3, which
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mediates responses to acidic and mechanical stimuli, is
located primarily in the Aβ-fibers that innervate the
skin and muscles.26 TRPV1 belongs to the TRPV sub-
family and is highly expressed in nociceptive Aδ- and
C-fibers.27 Previous studies have shown that the ASIC3
and TRPV1 receptors are involved in the peripheral
sensations of EA stimulation, based on their distribu-
tions and functional properties.28 The segmental analge-
sic effects of low-intensity EA are mediated by afferent
Aβ-fibers and ASIC3, and the systemic analgesic ef-
fects of high-intensity EA are attributed to the activa-
tion of Aδ/C-fibers and TRPV1. Other studies have
found that TRPV1 is highly expressed at Zusanli (ST
36), which suggests that TRPV1 might act as an acu-
puncture-responding channel that senses the physical
stimulation of acupuncture, conducts the signal to
nerve terminals through ATP-induced calcium wave
propagation (CWP),29 and mediates the transduction
of EA signals to the CNS. TRPV1 receptors are also ex-
pressed in subepidermal connective tissue cells, where
they may play a role in the effects of EA on local tis-
sue.30 TRPV1, as a mechanical sensitive channel, plays
an important role in the transmission of the physical
stimulation caused by acupuncture or EA to neurologi-
cal signaling in nervous system. In addition, the activa-
tion of TRPV1 receptors upregulates the expression of
protein kinases and related downstream molecules,
such as protein kinase A (PKA), protein kinase C
(PKC), and Phosphoinositide 3-kinase (PI3K)-protein
kinase B (PKB/Akt) signaling pathway, during com-
plete Freund's adjuvant (CFA)-induced inflammatory
pain. Furthermore, TRPV1 can activate the cellular sig-
naling pathways including the mitogen-activated pro-
tein kinase (MAPK) family member p38, extracellu-
lar-regulated protein kinase (ERK), c-Jun N-terminal
kinase (JNK), and downstream nuclear factor-κB
(NF-κB) and cAMP response element binding protein
(CREB) during CFA-induced pain. Moreover, nocicep-
tive Nav1.7 and Nav1.8 channels have been shown to
be sensitized under pain conduction in both the DRG
and SDH. Inflammatory factors, such as glial fibrillary
acidic protein (GFAP), S100 calcium-binding protein
B (S100B), and receptor for advanced glycation end
products (RAGE) are also involved in this process.31
TRPV1 also play a crucial role during EA-mediated an-
algesia. EA applied to Zusanli (ST 36) can significantly
attenuate TRPV1 activation and TRPV1-mediated the
above cellular signaling pathways, thus inhibiting the
transmission of nociceptive signals.32,33
Furthermore, under the chronic pain condition, the
plasticity of nociceptive neurons in both the PNS and
the CNS are also altered, which can result in peripheral
and central sensitization.34 Crosstalk between peripher-
al nociceptors and immune cells mediates peripheral
sensitization. Moreover, the neural, immune, and endo-
crine systems communicate with each other via inflam-
matory cytokines (Figure 1).35 Peripheral inflammatory
cytokines are potential messengers that mediate the
Figure 1 EA-induced neuroimmune and neuroendocrine modulation circuit
This circuit includes peripheral afferent and central efferent pathways. The nociceptive stimulus induced by CFA activates the no-
ciceptor and the vagal and sympathetic terminals in the peripheral afferent pathway. Meanwhile, immune cells form a crosstalk
mechanism among the nociceptor, vagal afferent fibers and sympathetic nerve terminal through the release of inflammatory cy-
tokines, such as TNF-α, interleukin-1β, and IL-6. The nociceptive signal is then transmitted to the spinal cord and brain. The modu-
latory signals received from the neural, immune, endocrine systems are then integrated in the brain, which further conveys sec-
ondary neuroimmune and neuroendocrine modulatory signals through the ascending and descending pain control pathway, the
VN, SN, and HPA) axis to regulate inflammatory pain. In the central efferent pathway, vagal efferent fibers and sympathetic pre-
ganglionic neurons act on the adrenal gland to release glucocorticoids and catecholamines, which further inhibit the release of
inflammatory cytokines and eventually mitigate anti-inflammatory pain. EA: electroacupuncture; TNF-α: tumor necrosis factor α;
IL-1β: interleukin-1β; IL-6: interleukin-6;VN: vagal nerve; SN: sympathetic nerve; HPA: hypothalamic-pituitary-adrenal.
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communication between nociceptors and vagal and
sympathetic nerves. Inflammatory cytokines, such as
tumor necrosis factor α(TNF-α), interleukin-1β
(IL-1β), and interleukin-6 (IL-6), are released by pe-
ripheral immune cells to form an "inflammatory
soup", and these cytokines bind with ion channel re-
ceptors, G protein coupled receptors (GPCRs) and ty-
rosine kinase receptors (Trk) that are expressed on noci-
ceptive neurons to mediate peripheral sensitization at
the cellular and molecular levels.4,36 However, inflam-
matory cytokines can also activate the afferent neurons
of the vagal nerve and sympathetic nerve endings
through a central neural circuit; the efferents of the va-
gal and sympathetic pre-ganglionic nerves then act on
the adrenal gland, immune cells or nociceptive neu-
rons, causing the release of norepinephrine (NE) and
acetylcholine (ACh), which inhibit the release of pe-
ripheral inflammatory cytokines.37,38
EA inhibits peripheral sensitization by modulating the
neural, immune and endocrine systems (Figure 2). At
the peripheral level, EA can inhibit the production and
release of inflammatory cytokines through various path-
ways. During inflammation, EA promotes peripheral
immune cells to release opioids, cannabinoids (CB)
and adenosine (A), which further exert anti-inflamma-
tory effects via binding with μ-opioid receptors or
CB2, A1 and A2A receptors that are expressed on noci-
ceptive neurons or immune cells, respectively, to inhib-
it the release of TNF-α, IL-1β, and IL-6.39-42 In addi-
tion to inflammatory cytokines, chemokines also play a
role in inflammatory pain. During the early stages of
inflammation, the chemokine (C-X-C motif) ligand
(CXCL) CXCL2 stimulates opioid release by acting on
the chemokine (C-X-C motif) receptor (CXCR) CX-
CR2 in neutrophils.43 Studies performed in a rodent
model of CFA-induced inflammation have also found
that EA applied to acupoint Huantiao (GB 30) upregu-
lates the expression levels of CXCL10 and CXCR3,
and then stimulates the release of opioids from macro-
phages.44 Macrophages have bidirectional effects on in-
flammatory responses. The M1 macrophage releases
pro-inflammatory cytokines, while the M2 macro-
Figure 2 Mechanisms of EA induced-analgesia and anti-inflammatory effects on inflammatory pain, involving interactions among
the neural, immune, and endocrine systems, at both peripheral and central levels
The injection of CFA/Formalin/Carrageenan/Collagen generates peripheral nociceptive signals to further sensitize the peripheral
nociceptive afferent fibers. Following its initial integration in the DRG, the nociceptive information is transmitted to the SDH and
supraspinal cord through the ascending pathway. Meanwhile, the SDH receives signals that are projected from the descending
pain modulatory system in the brain stem (PAG-RVM/LC-SDH pathway). In addition, the VN, SN, and HPA axis are involved in pain
processing and induce anti-inflammatory responses. EA: electroacupuncture; CFA: complete Freund's adjuvant; DRG: dorsal root
ganglion; SDH: spinal dorsal horn; PAG: periaqueductal grey; RVM: rostral ventromedial medulla; LC: locus coeruleus; VN: vagal
nerve; SN: sympathetic nerve; HPA: hypothalamic-pituitary-adrenal.
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phage secretes anti-inflammatory cytokines to inhibit
inflammatory responses.45 EA inhibits M1 macro-
phages, promotes the transformation from M1 to M2
macrophages, and consequently enhances the M2-me-
diated release of interleukin-10 (IL-10), which allevi-
ates inflammatory pain.46 The inflammasome NACHT,
LRR and PYD domains-containing protein 3 (NL-
RP3), a member of the NOD-like receptor (NLR) fam-
ily, is located on macrophages and modulates inflam-
mation and pain by promoting IL-1βmaturation.47 EA
can inhibit NLRP3 release by promoting the expres-
sion of CB2 and β-endorphin, thereby impeding the
maturation of IL-1βand mitigating inflammatory
pain.48 Adenosine exerts anti-inflammatory effects pri-
marily through the activation of A2A receptors in the
periphery.49 EA applied to the acupoints Zusanli (ST
36) and Sanyinjiao (SP 6) increased the levels of A2A
receptors, decreased the release of TNF-α, and simulta-
neously reduced inflammation and hyperalgesia in col-
lagen-induced arthritis model rats.42,50 EA may also act
through MAPK signaling pathways, such as the phos-
phorylation of ERK and JNK, to regulate the expres-
sion levels of TNF-αand IL-1βat both the transcrip-
tional and post-translational levels.51,52 In addition, EA
activates vagal and sympathetic nerves and the HPA ax-
is to inhibit the levels of inflammatory cytokines,
which may affect peripheral sensitization.3,53
Central efferent neuroimmune and neuroendocrine
modulation
The CNS includes the spinal cord and supraspinal
structures. The SDH is one of the major tissues that
regulate the transfer and processing of nociceptive sig-
nals. The lamina Ⅰ,Ⅱand Ⅴlayers of the SDH,
which contain a large proportion of intrinsic neurons,
intermediate neurons and projection neurons, primari-
ly receive projections from peripheral nociceptive Aδ-
and C-fibers and establish multiple synaptic connec-
tions. In addition, under peripheral sensitization condi-
tions, spinal microglia and astrocytes become activated,
releasing inflammatory mediators and forming synap-
tic connections with dorsal horn neurons.54,55 Nocicep-
tive signals in the SDH are transported to the brain
stem, thalamus, and cortex through projection neurons
and the ascending pathway (Figure 3). The SDH also
receives signals from the descending pathway that can
inhibit or facilitate the transduction of nociceptive sig-
nals.56 The change of synaptic plasticity in the SDH,
through neuroimmune interactions among spinal noci-
ceptive neurons, glial cells, and T lymphocytes, eventu-
ally results in central sensitization.57,58
The periaqueductal gray (PAG) and the rostral ventro-
medial medulla (RVM) are the major brain regions in-
volved in descending pain control. The analgesic ef-
fects of EA at the spinal cord level are also mediated by
descending inhibitory pathways, which regulate the re-
lease of classical neurotransmitters, such as opioids,
5-HT, norepinephrine (NE), and γ-aminobutyric acid
Figure 3 Anti-inflammatory and anti-nociceptive signaling
pathway induced by EA through peripheral, spinal, and su-
praspinal mechanisms during inflammatory pain
EA inhibited a variety of inflammatory mediators (TNF-α,
IL-1β, IL-6, NGF, and ATP) and promoted the peripheral re-
lease of opioid peptides, cannabinoids and adenosine to
suppress peripheral sensitization. In the spinal dorsal horn,
EA inhibited the postsynaptic excitation of NMDARs and
AMPARs, the MAPK phosphorylation-induced cellular signal-
ing, and the release of glial activation-dependent inflamma-
tory mediators to further attenuate central sensitization.
The EA-induced modulation of pain and inflammation at
the brain level also involves interactions among the central,
immune and endocrine systems. EA modulates the descend-
ing pain inhibitory pathway (PAG-RVM/LC-SDH) to induce
5-HT and NE expression in the SDH. In addition, the expres-
sion of peripheral inflammatory cytokines was regulated by
the HPA axis and the sympathetic and vagal nervous sys-
tems, which were associated with EA-induced neuroim-
mune and neuroendocrine modulations. EA: electroacu-
puncture; CFA: complete Freund's adjuvant; Tc: T lympho-
cyte cell; TNF-α: tumor necrosis factor α; IL-1β: interleu-
kin-1β; IL-6: interleukin-6; IL-17: interleukin-17; IL-10: inter-
leukin-10; IL-33: interleukin-33; P2XR: purinergic P2X recep-
tor; TRPV1: transient receptor potential vanilloid 1; CB: can-
nabinoids; CB2R: cannabinoids 2 receptor; CB1R: cannabi-
noids1 receptor; u-OR: u-opioid receptor; A1R: adrenergic 1
receptors; A2R: adrenergic 2 receptors; DRG: dorsal root gan-
glion; SCDH: spinal cord dorsal horn; SP: substance P; CGRP:
calcitonin-gene related peptide; 5-HT: 5-hydroxytryptamine;
5-HT1AR: 5-hydroxytryptamine 1A receptors; 5-HT2R: 5-hy-
droxytryptamine 2 receptors; NE: norepinephrine; μ-/δ-R: μ-/
δ-opioid receptors; GABA: γ-aminobutyric acid; GABAA/BR:
GABA A/B receptors; Glu: glutamate; α2AR: α2 adrenergic re-
ceptor; NMDAR: N-methyl-d-aspartate receptor; AMPAR: α
amino- 3-hydroxy -5- methyl-4-isoxazole-propionic acid; DA:
Dopamine; FNK: fractalkine; GPCRs: G protein-coupled re-
ceptors; PKC: protein kinase C; MAPK: mitogen-activated
protein kinase; NF-kB: nuclear factor-kB; CREB: cAMP re-
sponse element binding protein; RVM: rostral ventromedial
medulla; LC: locus coeruleus; PAG: periaqueductal grey.
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(GABA), and their corresponding receptors (Figure
2).10,21 Studies have demonstrated that CB1 receptors
are expressed on both GABAergic and glutamatergic
neurons in the PAG, which has different effects on as-
cending and descending pain modulation.59 EA can up-
regulate CB1 expression in GABAergic neurons, inhib-
iting GABA release from PAG neurons, and subse-
quently disinhibiting the release of 5-HT in the RVM,
which promotes the inhibition of chronic pain by de-
scending inhibitory pathways.60 Glial activation is re-
cruited during EA-mediated neuroimmune modula-
tion in the CNS. EA inhibits glial activation and reduc-
es the levels of inflammatory cytokines and other in-
flammatory mediators released by microglia and astro-
cytes, which suppresses central sensitization (Figure
2).61 Inflammation promotes ATP release and binding
with the P2X7 receptors on glial cells, which further ac-
tivates the chemokine fractalkine (FTK). FTK binds
with the receptor CX3CR to induce p38 phosphoryla-
tion, causing glial activation and the release of TNF-α,
brain-derived neurotrophic factor and other inflamma-
tory mediators, which modulate central sensitization.62
EA can inhibit the ATP-FTK-p38 signaling pathway
and suppress glial cell activation, thereby reducing the
expression levels of TNF-αand IL-1β.63 Excitatory glu-
tamatergic neurons, which primarily express α-amino-
3- hydroxy- 5- methyl- 4- isoxazole-propionic acid
(AMPA) and N-methyl-D-aspartate (NMDA) recep-
tors (NMDARs), promote the transmission of nocicep-
tive signals to the spinal cord and mediate central sensi-
tization. The NMDAR subtype NR1 plays a major
role during the regulation of NMDAR excitability,64,65
and the phosphorylation of NR1 promotes the central
sensitization. Inflammatory cytokines released by glial
cells, such as IL-1βand interleukin-17 (IL-17), also
promote the NR1 phosphorylation.66,67 EA inhibits the
IL-1β- and IL-17-induced NR1 phosphorylation in gli-
al cells, alleviating CFA-induced inflammatory pain.68
Moreover, EA also regulates the production and release
of TNF-α, IL-1β, neurokinin-1, and cyclooxygenase-2
at the transcriptional and post-translation levels
through spinal cell signaling pathways, such as the
PKA, PKC, and downstream NF-κB, and CREB path-
ways, which eventually inhibit central sensitization.69-73
At the supraspinal cord level, the brain stem, hypothal-
amus, thalamus, limbic system, cortex, and other im-
portant brain regions are integrated to manage pain in-
formation, including pain related sensory components,
anxiety, depression and other affective components,
which involves the comprehensive regulation of the
nervous, immune and endocrine systems in the brain
(Figure 2). On the one hand, EA regulates pain sensa-
tions and pain aversion through pain-related brain re-
gions in the CNS.74-77 On the other hand, the central ef-
ferents of the hypothalamic-pituitary-adrenal (HPA)
axis, and the sympathetic and the vagal nervous sys-
tems regulate the expression of peripheral inflammato-
ry cytokines (Figure 1).78-80 The adrenal gland is closely
associated with the process of EA-mediated neuroim-
mune and neuroendocrine modulation. The primary
glucocorticoid released from the adrenal cortex is corti-
sol in humans and corticosterone in rodents. The adre-
nal medulla releases catecholamines, including epineph-
rine, NE and dopamine (DA). Peripheral nociceptive
stimuli are transmitted through the spinal cord to the
paraventricular nucleus in the hypothalamus, which
further activates the HPA axis to release glucocorti-
coids and inhibit inflammatory responses.3,81 Previous
studies have demonstrated that EA stimulated the acti-
vation of the HPA axis to release glucocorticoids and
increased the levels of peripheral serum corticosterone,
while inhibiting the expression of inflammatory cyto-
kines, thus alleviating inflammatory pain induced by
CFA.82,83 The neuroimmune and neuroendocrine mod-
ulation induced by vagal and sympathetic nerves is pri-
marily mediated by the release of ACh and NE. The va-
gal nerve acts on the adrenal gland to release ACh
through the afferent nucleus tractus solitarius and the
efferent dorsal motor nucleus. ACh then binds to α7
nicotinic cholinergic receptors expressed on macro-
phages to inhibit the release of TNF-α.84,85 Sympathetic
preganglionic neurons may stimulate the adrenal gland
to release ACh, while postganglionic neurons directly
release NE, independent of the adrenal gland, via α2-/
β-adrenergic receptors in T lymphocytes, which fur-
ther inhibits inflammation. In addition, the postgangli-
onic neurons of the vagal nerve also inhibit the produc-
tion of inflammatory cytokines in the spleen by activat-
ing the sympathetic adrenergic splenic nerve via
a7nAChRs at the celiac ganglion. NE from the splenic
nerve activates T lymphocytes to inhibit cytokine pro-
duction in splenic macrophages.3,5,86 The application of
different EA frequencies results in the selective activa-
tion of sympathetic preganglionic and postganglionic
neurons, which results in different neuroimmune and
neuroendocrine modulatory effects.80 The vagal nerve
plays a role in EA-induced neuroimmune and neuroen-
docrine modulation.78,79 A previous study also suggest-
ed that EA application stimulated the vagal nerve
caused the adrenal gland to release DA, and decreased
TNF-αlevels in the serum and spleen.79 Furthermore,
vagotomy, adrenalectomy and splenectomy can affect
the neuroimmune and neuroendocrine modulation in-
duced by EA.78,79,83 Although the vagal nerve mediates
the anti-inflammatory effects of EA, the role of the va-
gal nerve during pain perception remains poorly under-
stood.
DISCUSSION
The mechanism underlying EA-mediated pain reduc-
tion is multifaceted, ranging from the activation of sin-
gle systems to multisystem connections. The nervous,
immune, and endocrine systems are fundamental to
the autoregulation of the body, and these systems are
all involved in the EA-mediated analgesia.3This article
745
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describes the anti-inflammatory and anti-nociceptive
response induced by EA application, with a particular
focus on the role played by neural-immune-endocrine
interactions during this process. During inflammation,
peripheral inflammatory cytokines sensitize nociceptive
neurons to transmit nociceptive signals to the spinal
cord and supraspinal cord. Meanwhile, through the
HPA axis and the sympathetic and vagal nervous sys-
tems, nociceptive signals can stimulate the release of
NE and ACh from the adrenal gland, inhibiting the ex-
pression of inflammatory cytokines and forming a neu-
roimmune and neuroendocrine modulatory circuit
(Figure 1). This circuit includes interactions among pe-
ripheral afferents and central efferents that are induced
by the application of EA and mediates the modulation
of the neuroimmune and neuroendocrine systems dur-
ing inflammatory pain. The immune cells and cyto-
kines sensitize the nociceptive neurons, which in turn
activate the immune response. Furthermore, the HPA
axis and sympathetic and vagal nerves inhibit inflam-
mation through interactions with immune cells and no-
ciceptive neurons, forming a feedback loop.3,5,36,87 The
peripheral afferent circuit includes crosstalk among im-
mune cells, inflammatory cytokines, peripheral noci-
ceptive neurons, the HPA axis, and sympathetic and va-
gal nerves. In central efferent pathways, changes in the
synaptic plasticity of spinal nociceptive neurons and gli-
al cells can lead to neuroimmune interactions. Further-
more, nociceptive signals in the neural, immune and
endocrine systems are integrated in corresponding func-
tional brain areas, further modulating the interactions
of neuroimmune and neuroendocrine under pain con-
dition. The anti-inflammatory and anti-nociceptive sig-
naling pathways are regulated by EA at the peripheral,
spinal, and supraspinal levels in inflammatory pain
models, and the mechanisms of EA-induced analgesia
are associated with the inhibition of peripheral and cen-
tral sensitization (Figure 2).21 Peripherally, EA inhibits
the release of pain-related inflammatory mediators dur-
ing inflammatory responses caused by tissue injury, the
expression of pro-nociceptive receptors in peripheral
neurons, and the phosphorylation of cellular signaling
pathways, all of which desensitize peripheral pain per-
ception. Furthermore, EA also promotes the release of
peripheral opioid peptides, cannabinoids and adenos-
ine to inhibit peripheral inflammatory pain. Centrally,
EA inhibits the activation of spinal cord excitatory neu-
rons, including NMDAR and AMPAR-mediated post-
synaptic excitation, the activation of MAPK phosphor-
ylation-induced cellular signaling pathways, the activa-
tion of glial cells, and the release of inflammatory medi-
ators, such as inflammatory cytokines, chemokines,
and ATP, thereby inhibiting central sensitization.10, 21 In
addition, EA enhances descending inhibitory pathways
to prohibit the transmission of pain. At the brain level,
EA modulates pain and inflammation through interac-
tions with the central nervous, immune and endocrine
systems. Furthermore, the peripheral inflammatory cy-
tokine-dependent anti-inflammatory response, mediat-
ed by the HPA axis and the sympathetic and vagal ner-
vous systems, is also involved during EA-mediated anal-
gesia (Figure 3).3Consequently, the multiple modulato-
ry effects of EA on inflammatory pain may be associat-
ed with neural-immune-endocrine interactions.
However, further studies on the EA-induced neuroim-
mune and neuroendocrine modulation of inflammato-
ry pain are required because the neuroimmune and
neuroendocrine modulation mediated by EA is not the
simple addition of EA-induced analgesia to anti-inflam-
matory effects; instead, this modulation represents an
integrated effect that requires interactions among the
nervous, immune and endocrine systems. This article
focused on the inflammatory cytokines that are in-
volved in the interactions among nociceptive neurons,
vagal afferent nerves and sympathetic nerve terminals.
Previous studies showed that crosstalk between sympa-
thetic nerve terminals and peripheral nociceptors in-
volves bradykinin, prostaglandin E2, nerve growth fac-
tor, and adrenaline, in addition to adenosine receptors,
which causes the sensitization of nociceptive neu-
rons.88-90 The vagal afferent nerve may have similar
properties to nociceptive neurons, including discrimi-
native responsiveness to potentially noxious physical
and chemical stimuli, peripheral sensitization and the
capacity to induce central sensitization.91,92 Future stud-
ies are necessary to explore other inflammatory media-
tors involved in nociceptor- and sympathetic/vagal
nerve-mediated neuroimmune and neuroendocrine
modulation to further clarify their roles during the po-
tentiation of inflammatory pain. In addition, although
there are several studies investigating the mechanism
through which EA acts on inflammatory pain in the
nervous system, mechanistic perspectives on the EA-in-
duced neuroimmune and neuroendocrine modulation
of inflammatory pain involving the HPA axis and the
sympathetic/vagal nervous systems are still lacking.
The elucidation of the mechanisms that underly the ef-
fects of EA on inflammatory pain from multiple per-
spectives may further contribute to the clinical practice
of pain management, and studying EA-mediated neu-
roimmune and neuroendocrine modulation is impor-
tant for inflammatory pain control.
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