Review Article Neural Acupuncture Unit: A New Concept for Interpreting Effects and Mechanisms of ...

24 Pages·2014·3.36 MB·English

HindawiPublishingCorporation
Evidence-BasedComplementaryandAlternativeMedicine
Volume2012,ArticleID429412,23pages
doi:10.1155/2012/429412
Review Article
Neural Acupuncture Unit: A New Concept for Interpreting Effects
and Mechanisms of Acupuncture
Zhang-JinZhang,1Xiao-MinWang,2andGrainneM.McAlonan3
1SchoolofChineseMedicine,LKSFacultyofMedicine,TheUniversityofHongKong,10SassoonRoad,Pokfulam,HongKong
2NationalInstituteofNursingResearch,NationalInstitutesofHealth,Bethesda,MD20892,USA
3DepartmentofForensicandNeurodevelopmentalScience,InstituteofPsychiatry,King’sCollegeLondon,London,UK
CorrespondenceshouldbeaddressedtoZhang-JinZhang,[email protected]
Received24September2011;Revised30November2011;Accepted1December2011
AcademicEditor:TokuTakahashi
Copyright©2012Zhang-JinZhangetal. This is an open access article distributed under the Creative Commons Attribution
License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly
cited.
Whenanacupunctureneedleisinsertedintoadesignatedpointonthebodyandmechanicalorelectricalstimulationisdelivered,
various neural and neuroactive components are activated. The collection of the activated neural and neuroactive components
distributedintheskin,muscle,andconnectivetissuessurroundingtheinsertedneedleisdefinedasaneuralacupunctureunit
(NAU).ThetraditionallydefinedacupointsrepresentananatomicallandmarksystemthatindicateslocalsiteswhereNAUsmay
contain relatively dense and concentrated neural and neuroactive components, upon which acupuncture stimulation would
elicit a more efficient therapeutic response. The NAU-based local mechanisms of biochemical and biophysical reactions play
an important role in acupuncture-induced analgesia. Different properties of NAUs are associated with different components
of needling sensation. There exist several central pathways to convey NAU-induced acupuncture signals, Electroacupuncture
(EA) frequency-specific neurochemical effects are related to different peripheral and central pathways transmitting afferent
signals from different frequency of NAU stimulation. More widespread and intense neuroimaging responses of brain regions
toacupuncturemaybeaconsequenceofmoreefficientNAUstimulationmodes.TheintroductionoftheconceptionofNAU
providesanewtheoreticalapproachtointerpretingeffectsandmechanismsofacupunctureinmodernbiomedicalknowledge
framework.
1.Introduction neuropsychiatric disorders [2]. Despite this, several funda-
mentalissuesremainunresolvedinacupunctureresearch.
Modern acupuncture can be defined as a therapeutic tech-
niqueinwhichsharp,thinneedlesareinsertedintospecific 1.1. Metaphysical Concepts of Acupoint and Meridian in
pointsonthebodywithmechanical,electrical,orotherphys- TCM. ThedoctrineofTCMwasoriginallydevelopedfrom
icalstimulation.Thenomenclatureandlocalizationofmost elementary anatomical knowledge obtained in early days
specific points, known as acupuncture points or acupoints, [4].Thisisevidencedinnumerousgrossanatomicalstudies
wereestablishedintraditionalChinesemedicine(TCM)dur- with measurement and a vast number of anatomical terms
ingaboutB.C.400–A.D.1740s.Overthepastfourdecades, recorded in ancient TCM bibliographies. Ancient doctors
numerousclinicalobservationsandstudieshaveshownthat hadobservedperipheralnervetrunks,branches,andplexus
acupuncture therapy possesses broad therapeutic benefits widely distributed in the superficial and deep tissues as
[1,2].Alargebodyofexperimentalevidenceobtainedinani- well as on visceral organs, referring to as “meridians” and
malsandhumansubjectsprovidesmanyinsightsintoneural “collaterals” (Jing and Luo in Chinese). They believed that
mechanisms of acupuncture effects, in particular acupunc- the meridians with the collaterals constitute an extensive
ture analgesia [3]. Today, this ancient healing technique is network that communicates all parts of the body via the
increasinglyintroducedintoclinicalpractice,particularlyfor meridianenergy(Jing-QiinChinese).Themeridianenergy
2 Evidence-BasedComplementaryandAlternativeMedicine
can flow onto specific loci, termed “convergences” or “con- an alternative concept that substantially differentiates from
junctions”inancienttermsand“acupoints”today.Thedoc- the metaphysical concept of acupoint. Such concept would
trine of TCM clearly states that acupoints are not the skin, provideamoreaccuratetermandanewtheoreticalapproach
muscles, connective tissues, or bones, but local sites where tointerpretingeffectsandmechanismsofacupuncture.
the meridian energy effuses onto the superficial tissues and
infusesintothedeeptissuesandvisceralorgans[4].
2.TheDefinitionofNeuralAcupunctureUnit
Ancient doctors also had observed that pathological
(NAU)andItsDifferentiationfromAcupoint
conditions occurred in the deep tissues and visceral organs
can be manifested as pain or tender points on the body,
Insertion into the skin with filiform needles is the most
calledA-Shipoints.Thelocalizationsandclinicalindications
commonlyusedformofacupuncturestimulationinclinical
formostmeridian-basedacupointswereinitiallydeveloped
practice.Whenafiliformneedleisinsertedintoadesignated
fromA-Shipoints.Ancientdoctorssuggestedthatstagnation
point on the body and mechanical (manual manipulation)
ofthemeridianenergyisadeterminingfactorinthepatho-
orelectricalstimulationisdelivered,avarietyofneuraland
genesisofdiseases.Needling,moxibustion,andotherforms
neuroactive components are activated. A collection of the
of stimulation on acupoints were considered to improve
activatedneuralandneuroactivecomponentsdistributedin
pathologicalconditionsbyunblockingthestagnationofthe
the skin, muscle, and connective tissues surrounding the
meridian energy and rearranging the balance of Yin and
inserted needle is defined as a neural acupuncture unit
Yang,thatis,homeostasis.
(NAU). Here, the designated points include not only the
Itwouldseemthatthemetaphysicalconceptsofacupoint traditionally defined acupoints, which are often called as
andmeridianrepresentanentitywithparticularanatomical meridian-based acupoints or acupoints in short, but also
and physiological neural profiles. Nevertheless, how to pre- A-Shi points and control points (sometimes called non-
cisely elucidate the metaphysical concepts of acupoint and acupoints or placebo points) as specifically designated in
meridianintheframeworkofmodernbiomedicalknowledge acupunctureresearch.
hasbeenakeyissueinacupunctureresearch. Apparently, NAU is a hypothetical concept that repre-
sentslocalneuralandneuroactivecomponentsinthephys-
iological,biochemical,andtherapeuticresponsetoneedling
1.2. “Specific” and “Nonspecific” Properties of Acupoints. As
stimulation, rather than localization of the stimulation. On
acupoints are deemed “specific” points in the doctrine of
TCM, many efforts have been made to identify their “spe- theotherhand,viewedfromancientandmodernanatomical
cific”properties.Potentialdifferencesbetweenthetradition- perspective[4],thetraditionallydefinedacupointscouldbe
defined as an anatomical landmark system that indicates
ally defined acupoints and so-called “nonacupoints” have
local sites where NAUs may contain relatively dense and
beenexaminedatanatomical,histological,biochemical,and
concentrated neural and neuroactive components, upon
electrophysiologicallevelsinbothanimalsandhumansub-
whichacupuncturestimulationwouldelicitamoreefficient
jects[4].Althoughearlystudiesindicatethatmostacupoints
therapeutic response comparedtononacupoints. Intheory,
are located on or adjacent to peripheral nerve trunks or
thereareinnumerableNAUsexistinginthebodyasacupunc-
branches,andthemeridianscorrespondwithtrajectoriesof
tureprocedurecanbeperformedindifferentdirectionsatthe
relevant peripheral nerves [4], there is no convincing evi-
samepointandonmostareasofthebody,includingmyriad
dencetosupporttheexistenceofnovelorspecialstructures
A-Shi points and 361 WHO-defined standard acupoints
beneathacupoints.However,histologicalstudiesindeedhave
[6]. The pattern of NAUs varies, mainly depending upon
revealed a relatively dense and concentrated distribution of
designatedpointsandacupuncturestimulationmodeaswell
certain neural and neuroactive components beneath many
as needling direction and depth. A hypothetical NAU is
acupoints commonly used in clinical practice compared to
illustratedinFigure1.
adjacent areas [4]. Electrophysiological studies also have
shown that the skin along with acupoints and meridians
may possess distinct electrical properties which are closely 3.MajorNeuralandNeuroactive
associated with the activity of local neural and neuroactive
ComponentsofNAUs
components [5]. These results suggest the relativity of the
“specific”and“nonspecific”propertiesofacupoints. 3.1.NeuralComponents. Earlystudiesinanimalsandhuman
Thedefinitionandidentificationofthepatternof“spe- autopsies revealed that most acupoints contained abun-
cific”and“nonspecific”neuralandneuroactivecomponents dant free nerve endings, encapsulated cutaneous receptors
in the response to acupuncture stimulation would help us (Merkel,Meissner,Ruffini,andPaciniancorpuscles),sarcous
betterunderstandtheessentialmechanismsofacupuncture sensoryreceptors(musclespindlesandtendonorgans),and
anddevelopmoreefficientacupuncturestimulationmodes. their afferent fibers [4]. Somatic efferent fibers innervating
However,themetaphysicalconceptofacupointandmeridian muscles,smallnervebundles,andplexuswerealsoobserved
itselfcannotprovidesufficientinformationfordefiningand in acupoint tissues, but no novel structures were found
identifyingtheresponsepattern.Interactionsbetweenneural beneathacupoints.Manyacupointsexaminedhadrelatively
andneuroactivecomponentsaswellastherelationshipwith dense neural components, particularly nerves fibers, with a
thelocalandcentralresponsetoacupuncturestimulationare ratio of nearly 1.4:1 compared to non-acupoint areas [7–
alsonotwellelucidated.Thus,itwasnecessarytointroduce 9].Theratiooflocalmyelinatedtononmyelinatedfiberswas
Evidence-BasedComplementaryandAlternativeMedicine 3
Cutaneous afferent nerve
Free nerve endings
Merkel disc ending Lymph vessel
Meissner’s corpuscle Vein
Ruffini’s corpuscle Artery and arterioles
Pacinian corpuscle Nerve and branches
Muscle spindles
Figure1:Arepresentativemuscle-spindle-richNAUintheresponsetomanualtwistsofacupuncturestimulation.TheNAUwiththerelated
neural and neuroactive components is illustrated as the dotted line-defined vase-like pattern, which is principally determined by twist-
produceddifferentdistanteffectsonmechanoreceptorslocatedincutaneousandmuscletissues(seeSection5.1).
found to be nearly 4-fold higher than surrounding areas in fibers(seebelow).Table1summarizesmajornon-neuronal
humanZu-San-Li(ST36)[9,10].Asimilarphenomenonwas cell-released neuroactive mediators and their correspond-
alsorecordedinrats,showingthatsarcoussensoryreceptors ing receptors. Based on their effects on afferent fiber
andtheirafferentfibersareconcentratedatacupointslocated excitability of NAUs, the mediators can be classified as
onthickmuscles[11]. inhibitoryandstimulatory.Theinhibitorymediatorsmainly
AnotherimportantneuralcomponentofNAUsisdense include acetylcholine, noradrenaline (NA), γ-aminobutyric
andfineautonomicnervefibers[12].Acloseapproximation acid (GABA), β-endorphin, SP, somatostatin, nitric oxide
of autonomic fiber varicosities and somatic afferent fiber (NO), ATP/cGMP, and adenosine, which suppress afferent
terminals is often observed in rabbit acupoint areas [12]. fiber excitability of NAUs. Most cytokines, prostaglandins,
Mostautonomicnervesarenoradrenaline-(NA-)containing bradykinin, and other proinflammatory factors are stimu-
sympatheticfibers,andaninteractionbetweensomaticand latory mediators that directly or indirectly enhance afferent
autonomicneuralcomponentsmayservetomodulatelocal fiber excitability of NAUs. Serotonin (5-HT) and histamine
andafferentsignalsinNAUs(seebelow). canexerteitherinhibitoryorstimulatoryeffects,depending
uponwhichreceptorstheyacton(Figure2).
3.2.NeuroactiveComponentsandRelatedMediators. Broadly
speaking,neuroactivecomponentsofNAUscanbedefinedas 4.BiochemicalReactionsofNAUs
nonneuronaltissuesandcellsthatreleasevariousmediators
capable of modulating afferent fiber transmission of NAUs. When an acupuncture needle is inserted into a designated
point and repetitively manipulated in different directions,
The most apparent neuroactive components are mast cells,
it is assumed to cause local tissue injury and biochemical
sympathetic nerve-rich blood vessels, and small lymphatic
reactions, with the release of various inflammatory and
vessels[4].Inaddition tomastcellsthatreleasemanyneu-
immunemediatorsinNAUs.Nevertheless,unlikemostother
roactive mediators, including histamine, substance P (SP),
forms of tissue injury, acupuncture-induced tissue injury
and other immune factors via a degranulation mechanism
may represent a “positive” biochemical process resulting in
inresponsetoacupuncturestimulation[13–15],othernon-
therapeutic responses at local and systemic levels. This is
neuronalcells,includingmacrophages,fibroblasts,lympho-
considered due to a robust axon reflex and modulation of
cytes, platelets, and keratinocytes are also involved in the
modulation of local and afferent signals of NAUs. These afferentfibertransmissioninNAUs.
cellsreleasevarioustransmitters,modulators,inflammatory
and immune factors, which directly or indirectly act at 4.1. Acupuncture-Induced Robust Axon Reflex in NAUs. The
correspondingreceptorsonthesurfaceofperipheralafferent axon reflex is a response to peripheral tissue injury, which
4 Evidence-BasedComplementaryandAlternativeMedicine
Table1:Majornon-neuronalneuroactivemediatorsinvolvedinthemodulationofNAUafferentfiberexcitability.
Non-neuronalcellsreleasingneuroactive ReceptorsandactionsonNAU Effects on NAU affer-
Mediators Reference
mediators afferentfiberterminals entfiberexcitability
Serotonin(5-HT) Platelets,mastcells 5-HT receptor + [17]
3
5-HT receptor – [203]
1
Mainlyreleasedfromsympatheticnerve
Noradrenaline(NA) varicosities.Epidermalcellsmaybe α Receptors – [51]
2
NA-storingcells.
Keratinocytesandinjuredefferentfiber
Acetylcholine MuscarinicM receptor – [204]
terminals 2
Histamine Mastcells H receptor – [17]
3
H receptor +
1
Glutamate/aspartate Allskinepithelialcellsandmacrophage Autoreceptors(?) –(?) [35,36,205]
γ-aminobutyricacid
Macrophagesandlymphocytes GABA receptors – [206,207]
(GABA) A
Keratinocytes,melanocytes,dermal
β-endorphin μ-opiatereceptors – [47,48,208]
fibroblasts,andleukocytes
Mastcells,fibroblasts,platelets,
SubstanceP(SP) Autoreceptor(?) –(?) [14,37,38,46]
keratinocytes,andmacrophages.
Calcitonin
gene-relatedpeptide Epithelialcells,Tcells,macrophages Autoreceptor(?) –(?) [39,209,210]
(CGRP)
Somatostatin(SS) Merkelcells,keratinocytes SSreceptors – [21,211–213]
InhibitsSPreleasefromprimary
NitricOxide(NO) Localtissues afferentterminalsandenhances – [50,214,215]
acetylcholineandβ-endorphin.
ATP/cGMP Epidermalcells P2XandP2Yreceptor – [31,214,216]
DegradedfromATPreleasedinresponseto
Adenosine A receptor – [31]
mechanical,electrical,orheatstimulation. 1
Bradykinin Localtissuesandcells B1/2receptors + [217–219]
Cytokines(IL-1β,
Stimulateafferentfibersand
IL-6,IL-8,and Localtissuesandcells + [217–221]
augmenttheirexcitability
TNF-α)
Inhibitstheproductionof
Cytokines(IL-4and
Localtissuesandcells inflammatorypainsignalsin – [220,222]
IL-10)
afferentterminals
Prostaglandins Localtissuesandcells EPreceptors + [221,223]
aQuestionmarks(?)indicatetobedetermined.
produces an impulse that moves from one nerve branch to bynervesfromtotallydifferentspinalsegments,becominga
other branches in close contact with nonneural tissues, redlineaccompaniedbythepropagationoftheneedlingsen-
mainlybloodvessels,sweatglands,andmastcells[16].This sation.Thisphenomenoniscalledthepropagatedsensation
resultsinvasodilatationandreleaseofvascularandneuroact- alongmeridians(PSM),whichoccursin0.3%ofthehealthy
ivemediatorsfromimmunecellsleakingfromdilatedvessels population[18].
[17].Itiswelldocumentedthattheaxonreflexplaysacentral The robust axon reflex of NAUs and PSM observed
role in immune-nerve crosstalk, especially in neurogenic during acupuncture stimulation may be closely related to
inflammation[17].Clinicalobservationshavedemonstrated dense sympathetic nerve-rich arterioles, lymphatic vessels,
that acupuncture-induced axon reflex is strongly apparent andmastcellsaswellasconcentratedprimaryafferentfibers
in acupoint areas, particularly in the back and abdominal in NAUs [4, 19]. The acupuncture-induced robust axon
acupoints. It is characterized by a hyperemia (flare) that reflexismorelikelyduetotransientvasodilatationandtem-
rapidly(generallywithin2–5min)spreadsbeyondneedling porary neural communication between adjacent branches
points of the skin with a diameter of 1–3cm (Figure3(a)). of nerves from different spinal segments via vascular and
Moreover, the acupuncture-evoked flare sometimes can neural mediators released from neural and nonneuronal
spreadalongameridianacrossseveraldermatomessupplied tissues(Figure3(b))[15,20,21].Apparently,therobustaxon
Evidence-BasedComplementaryandAlternativeMedicine 5
Epidermal MacrophageMelanocyte Merkel cell
Platelets cells Fibroblast Mast cells Keratinocyte
Arteriole with
NA fibers Leukocytes
Lymph cells
IL-1β, IL-6, IL-4,
BKs PGs ATP/NA Glu 5-HT His SP AChGABAβ-ENDCGRP SSIL-8,TNF-α IL-10
CGMP
Adenosine
No
?
? ?
− + +
SP
+
P2X/α2-R Auto-R 5-HT15-HT3H1 H3Auto-RM2 GABAA μopioidAuto-R −
B1/2 Ep A1 P2Y SSR
Afferent fiber
terminal
Figure2:Schematicillustrationofmajornonneuronalneuroactivemediatorsandtheircorrespondingreceptorsinvolvedinthemodulation
of NAU afferent impulses. Molecules in red, green, and violet color represent stimulatory, inhibitory, and both effects on afferent
fiber excitability, respectively. Autoreceptors to be identified are indicated with question symbols (?). A , adenosine A receptor; ACh,
1 1
acetylcholine;Auto-R,autoreceptor;B1/2,bradykininreceptors1and2;BK,bradykinin;CGRP,calcitonin-gene-relatedpeptide;β-END,
β-endorphin;EP,prostaglandinEreceptor;GABA,γ-aminobutyricacid;Glu,glutamate;H /H ,histamineH /H receptors;His,histamine;
1 2 1 2
5-HT,5-hydroxytryptamine;IL,interleukin;M ,muscarinicM receptor;NA,noradrenaline;NO,nitricoxide;PG,prostaglandins;P2X/P2Y,
2 2
purinergicreceptorsP2XandP2Y;α -R,α adrenoceptor;SP,substanceP;SS,somatostatin;SSR,somatostatinreceptor;TNF-α,tumor
2 2
necrosisfactor-α.
reflexplaysanimportantroleintheproductionoflocaland afferents,whichdevelopsynapse-likecontactswithpostgan-
afferentsignalsinNAUs[19]. glionicsympatheticnervevaricosities,whereNAreleaseacts
on α-adrenoceptors on afferent nerve terminals of NAUs
4.2. Local Modulation of NAU Afferent Impulses by Neuro- [22,23].
active Mediators. In response to acupuncture-caused tissue Althoughacupuncture-causedtissueinjurycouldinduce
injury,mastcells,platelets,andotherimmunecellsmigrate the release of both inhibitory and stimulatory mediators
tomakeclosecontactwithafferentnerveterminalsinNAUs. fromnon-neuronalcellsinNAUsviatherobustaxonreflex,
Theinjuredandmigratedcellsconsequentlyreleasevarious as shown in Table1, inhibitory mediators released may
neuroactive mediators, which infiltrate the tissues and act predominate over stimulatory mediators. Several lines of
at corresponding receptors on the surface of afferent nerve evidenceindicatethatthepredominanteffectofacupuncture
terminals in NAUs via the axon reflex [17]. Meanwhile, istoenhancetheactivityofinhibitorymediatorsunderpain
tissueinjuryresultsinplasticchangesinperipheralprimary conditions. First, compared to most other tissue injuries,
6 Evidence-BasedComplementaryandAlternativeMedicine
Skin
Stlmulus
Neuroactive
mediators
5 cm
Recording
(a) (b)
Figure 3: Acupuncture-induced robust axon reflex (a) and its involvement in the propagated sensation along meridians (PSM) (b).
In (a), hyperemia (flare) was induced by acupuncture needling in acupoint areas of Bladder Meridian Foot Taiyang in the back. (b)
illustratesputativecommunicationbetweenadjacentbranchesofnervesfromdifferentspinalsegmentsvianeuroactivemediatorsreleased
byacupuncturestimulationfromneuralandnon-neuronaltissues.(b)wasreproducedbasedontheworkdonebyProfessorZhao’sresearch
groupwithhisgenerouspermission(alsosee[20,21,224]).
acupuncture-caused tissue injury is minimal. This may tissues are believed to at least partly come from non-
mean that the release of proinflammatory factors, most of neuronal cells, accounting for nearly 50% of total levels
which enhance NAU afferent fiber excitability, is limited. of SP in rodent peripheral tissues [45, 46]. The elevation
On the other hand, a large number of studies have shown of non-neuronal mediators activates the negative feedback
thatacupuncturesignificantlyelevatestheconcentrationsof mechanismbyactingatcorrespondingautoreceptorsand,in
many non-neuronal cell-released neuroactive mediators in turn,suppressesafferentfiberexcitabilityofNAUs.
local tissues at acupoints, especially including NA [24–26], Taken together, it can be assumed that, in addition to
β-endorphin [27, 28], somatostatin [29], and acetylcholine central mechanisms, NAU-based local mechanisms play an
(ACh) [30], all of which suppress afferent fiber excitability equally important role in acupuncture analgesia, via which
of NAUs. Second, it is generally accepted that acupuncture afferent noxious signals from sites distal to needling points
is not only a noxious stimulus but is also mechanical and are blocked mostly by enhancing the activity of inhibitory
can be electrical (see below). Many inhibitory mediators, mediators and activating the autoreceptor-based negative
such as ATP and its metabolite adenosine, are released feedback in NAUs. There have been many studies proving
in response to mechanical and electrical stimulation [31]. the NAU-based local mechanism of acupuncture analgesia.
Acupuncturestimulationhasbeenfoundtorobustlyincrease A recent study found that, while manual acupuncture
the extracellular concentrations of ATP and adenosine in on rat Zu-San-Li (ST36) produced pronounced analgesic
mice’s acupoint tissues, while analgesic effects were elicited effects, it also enhanced the degranulation of mast cells in
[31]. local acupoint tissues; however, the analgesic effects were
Lastly, it is well known that a majority of peripheral completely abolished by local injection of disodium chro-
small-diameterafferentfibersofthespinalandcranialnerves moglycate, an inhibitor of mast cell degranulation, indi-
usetheexcitatoryaminoacidglutamate(Glu)asatransmit- cating the involvement of mast cell-released mediators in
ter [32, 33]. Most Glu-containing afferent fibers cocontain acupuncture analgesia [15]. Local injection of naloxone,
oneormorepeptides.SubstanceP(SP)andcalcitoningene- an opioid receptor antagonist, an antibody against β-
related peptide (CGRP) are the most common peptides endorphin,orcorticotropin-releasingfactorantagonistalso
that are colocalized in a majority of afferent fibers [34]. eliminatedanalgesicpotencyofelectroacupuncture(EA)in
Many non-neuronal cells also synthesize and release Glu, animalmodelsofacuteandchronicinflammatorypain[47,
SP, and CGRP as shown in Table1. It has been proposed 48]. Likewise, subcutaneous acupoint injection of neostig-
that peripheral afferent fibers bear autoreceptors for Glu mine,acholinesteraseinhibitor,significantlyenhancedpain-
[35, 36], SP [37, 38], and CGRP [39]. A number of studies relievingeffectsofEAinrats[30].Thesestudiessuggestthat
in rats and humans have shown that electroacupuncture the local β-endorphin and ACh play a key role in the local
increased the quantity of CGRP [40–42] and SP [42–44] mechanismofanalgesiceffectsofacupuncture.
in peripheral tissues and in blood circulation, although the Most recently, it was found that, while acupuncture
effectsonlocalnon-neuronalglutamateandotherexcitatory on mice’s Zu-San-Li (ST36) significantly reduced chronic
transmitters are unclear. The increased mediators in local pain in the ipsilateral paw and increased the extracellular
Evidence-BasedComplementaryandAlternativeMedicine 7
concentrations of ATP and adenosine in acupoint tissues, theinsertedneedlewouldbeexpectedtoproducemechanical
thelocalapplicationof2-chloro-N(6)-cyclopentyladenosine pressureandtissuedistortionthatactivateNAUmechanore-
(CCPA), an adenosine A receptor agonist, replicated the ceptorslocatedintheskin,muscle,andtendontissues[58–
1
analgesic effect of acupuncture. The local inhibition of 63].Thismechanicaleffecthasbeenwellconfirmedinrecent
enzymesinvolvedinadenosinedegradationalsopotentiated studiesofbothmiceandhumansubjects[64,65].
theacupuncture-elicitedincreaseinadenosine,aswellasits It is well documented that the distant effect is mainly
antinociceptive effect [31]. These data strongly suggest that achieved by shear force- and stress-induced tissue displace-
acupuncture-released ATP and its metabolite adenosine in ments during manual manipulation [63–65]. All types of
local acupoint tissues block pain impulses from sites distal manualtechniquestestedhaveyieldedgreaterdistanteffects
toneedlingpoint. onsarcousstretchreceptorsthancutaneousmechanorecep-
tors; twist/rotation has the greatest distant effects on the
4.3.TheRelationshipbetweenNAUsandElectrodermalProp- cutaneous superficial and deep receptors as well as sarcous
ertiesofAcupoints. Itiswelldocumentedthatmanyimmune stretch receptors compared to other techniques in rabbits
mediators, in particular, local tissue-released NA, nitric (Figure4)[58,59].Theorderofthedistanteffectsoftwist/
oxide (NO), tumor-related factors, and mast cell-released rotation is sarcous stretch receptors, cutaneous superficial
histamineand5-HT[15,24,49–52],areheavilyinvolvedin mechanoreceptors, and deep pressure-detected receptors.
the determination of electrical properties of acupoints and Basedonthisorder,thetwist-associatedmuscle-spindle-rich
meridians, namely, higher conductance, lower impedance, NAUscanbeproposedtobeavase-likepatternasillustrated
and higher capacitance compared to adjacent tissues [5]. inFigure1.
Electrodermalmeasureshavebeenshowntobesignificantly All types of manual techniques tested can activate Aα,
associatedwithclinicaloutcomesofacupuncturetreatments β, and δ fibers of NAUs. Twist/rotation additionally excites
inpatientswithchronicpelvicpain[53].Acupuncturestim- C-fibers on most occasions, whereas other types of manual
ulation was found to change the human skin sympathetic techniquesseldomdoso[62,66].
nerveactivity[54].Normalizationofskinelectricalconduc-
tanceatrelatedacupointshasalsobeenlinkedtotherapeutic
5.2.Electroacupuncture-(EA-)InducedDistantEffects. Elec-
responses to acupuncture in subjects with heart stress [55],
troacupuncture(EA)stimulationproducesthedistanteffects
obesity[56],andacutejointinjury[57].Theseobservations
inexcitingcutaneousmechanoreceptorsandsarcousstretch
suggest that normalization of electrodermal properties at
receptors of NAUs, with a range of nearly 25–45mm from
acupoints is perhaps associated with the modulation of
needling point. The EA intensity-dependent distant effect
neuroactivemediatorsinacupuncturestimulation.Whether
was observed on only the cutaneous superficial receptors,
electrodermalmeasuresofacupointscouldserveasareliable
but not the cutaneous deep receptors and sarcous stretch
and valid approach in detecting biochemical properties of
receptorsinrabbits(Figure5)[60,61].
NAUsdeservesfurtherinvestigation.
Collectively, while most nociceptors are innervated by
thinmyelinatedAδ andCfibers,mostsomaticmechanore-
5.BiophysicalReactionsofNAUs ceptorsareinnervatedbyAβfibers.Therefore,theactivation
ofmechanoreceptorsandtheirAβafferentfibersappearsto
As mentioned above, acupuncture is not only a noxious
play a dominant role in the biophysical reactions of NAUs,
stimulusbutcanincludemechanicalandelectricalstimula-
particularlyinmuscle-spindle-richNAUs.
tion. Thus, apart from biochemical reactions, acupuncture
also elicits biophysical reactions in NAUs. Early studies in
rabbits have examined the responses of different types of 6.NAUClassificationandItsDifferentialEffects
NAUmechanoreceptorstodifferentmanualtechniquesand
intensitiesofelectricalstimulation[58–62].Thestudieshave 6.1.ClassificationofNAUs. Itiswelldocumentedthatsoma-
revealed that the activation of the mechanoreceptors is not tosensoryreceptorsandtheirafferentfibersplaythecentral
necessarilylimitedsurroundingneedlingpointbutalsocan role in the production of NAU afferent impulses [3]. Based
spreadtoadistancefromneedlingpointandthisisreferred onthepredominanceofsomatosensoryreceptors,NAUscan
toas“distanteffect.”Moreover,therearehighnegativelinear be roughly classified into the three types: muscle-spindle-
correlations between the number of the activated receptors rich NAUs, cutaneous-receptor-rich NAUs, and tendon-
anddistancefromneedlingpoint(seeFigures4and5).The organ-rich NAUs. Table2 summarizes the definition, char-
distant effect is, therefore, a most important component of acteristics,andrelatedacupointsofthethreetypesofNAUs.
thebiophysicalreactionsofNAUs.
6.2. Differential Properties of Afferent Impulses Produced in
5.1.ManualAcupuncture-(MA-)InducedDistantEffects. In Different Types of NAUs. It is generally accepted that NAU
acupuncture practice, manual manipulation is often per- afferentimpulsesareinitiallyproducedthroughbiochemical
formed on the inserted needles to enhance needling sensa- and biophysical reactions and transmitted dominantly by
tion and therapeutic responses. The most commonly used thin fibers (Aδ and C fibers) and thick fibers (Aβ fibers),
manualtechniquesincludelift,thrust,twist,rotation,shake, respectively.Theimpulsesrepresenttherapeuticinformation
scrape, and flick. Gentle and repetitive manipulation onto thatmainlyconsistsofboth“positive”tissueinjury-induced
8 Evidence-BasedComplementaryandAlternativeMedicine
Number of activated receptors (%)2211505050 Number of activated receptors (%) 432100000
0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35
Scrape Lift/thrust Scrape/flick
Flick Twist/rotation Shake/lift/thrust
Shake Twist/rotation
(a) (b)
%) 20
ors (
pt 15
e
c
e
d r
e
at 10
v
cti
a
er of 5
b
m
u
N 0
0 20 40 60 80 100 120 140 160 180 200 220
Distance from acupuncture needling point (mm)
Scrape/flick
Shake/lift/thrust
Twist/rotation
(c)
Figure4:Thedistanteffectsofdifferentmanualtechniquesofacupunctureinactivatingcutaneoussuperficialmechanoreceptors(a),deep
pressure-detectedreceptors(b),andmusclestretchreceptors(c)locatedintheposterioraspectofthelegofBladderMeridianFootTaiyang
inrabbits.Percentofthenumberoftheactivatedreceptorsineachdefinedareasurroundingneedlingpointwascalculatedfromthetotal
numberoftheactivatedreceptors.Theplotswereproducedbasedonthedatareportedin[58,59].
and mechanoreceptor-activated signals. However, the pre- In contrast, for most cutaneous-receptor-rich NAUs,
dominant components may vary, largely depending upon forexample,Ren-Zhong(GV26)andShi-Xuan(EX-UE11),
different types of NAUs. For most muscle-spindle- and which are often used as consciousness-awakening, spirit-
tendon-organ-rich NAUs, the stretch receptor-activated quieting,andmind-stabilizingacupointsforacuteandsevere
signals dominate NAU afferent impulses. This assertion is neuropsychiatricconditions,suchassummerstroke,shock,
supported by an early study on acupuncture analgesia in coma,acutefever-causedconvulsion,trance,manicepisode,
healthy volunteers, revealing that increased pain threshold and severe depression, the treatment effects are closely
produced by manual acupuncture at He-Gu (LI4) was associatedwithpatients’strongfeelingofsharppainevoked
completely reversed by blockade of deep nerve branches byprickingontheacupoints[71].Itappearsthat“positive”
innervatingmusclefibers,butnotcutaneousnervebranches tissueinjury-inducedsignalstransmittedbysmall-diameter
[67].Similarphenomenawerealsoobservedinacupuncture afferent fibers (mainly Aδ and C fibers) may dominate
modulation of visceral functions in anesthetized rats, re- afferentimpulsesfromcutaneous-receptor-richNAUs.
vealing that arterial blood pressure and heart rate were
significantly reduced by manual acupuncture on acupoints
with the muscles alone, but not the skin alone [68, 69]. 6.3. The Relationship between NAU Properties and Compo-
Likewise, bidirectional rotation of a needle deeply inserted nents of Needling Sensation. A large body of empirical and
into a muscle-spindle-rich NAU beneath the human acu- experimental evidence confirms that acupuncture stimula-
pointShou-San-Li(LI10)producedgreaterneedlesensation tion with and without accompanying needling sensation
intensities compared to superficial needle insertion with (De-Qi in Chinese) leads to notable differences in neu-
mockdeeppenetrationandbidirectionalrotation[70]. roimaging[72,73],electroencephalogram[74],andclinical
Evidence-BasedComplementaryandAlternativeMedicine 9
%) 40 %) 80
mber of activated receptors ( 1122335050505 mber of activated receptors ( 12345670000000
Nu Nu 0
0
0 5 10 15 20 25 30 0 5 10 15 20 25 30
(a) (b)
45
%)
ors ( 3450
pt
ce 30
e
d r 25
e
vat 20
cti
a 15
of
er 10
b
m 5
u
N 0
0 5 10 15 20 25 30 35 40 45 50
Distance from acupuncture needling point (mm)
20 V
30 V
40 V
(c)
Figure5:Thedistanteffectsofdifferentintensitiesofelectroacupuncture(EA)inactivatingcutaneoussuperficialmechanoreceptors(a),
deeppressure-detectedreceptors(b),andmusclestretchreceptors(c)locatedinrabbittricepssuraemuscleareasofBladderMeridianFoot
Taiyang.Percentofthenumberoftheactivatedreceptorsineachdefinedareasurroundingneedlepointwascalculatedfromthetotalnumber
oftheactivatedreceptors.Theplotswereproducedbasedonthedatareportedin[60,61].
Table2:ClassificationofNAUsbasedonapredominanceofsomatosensoryreceptors.
Type Definitionandcharacteristics Relatedacupoints
Whenanacupunctureneedleisinserted,alarge Nearly60%acupointslocatedonthickmuscleareas
portionoftheinsertedneedlebodyissurroundedby containthistypeofNAUs,forexample,Zu-San-Li
Muscle-spindle-rich musclefibers.Musclespindlesarethemajorneural (ST36),He-Gu(LI4),andHuan-Tiao(GB30).Most
NAUs componentsinthistypeofNAUs.Thereareabout acupointscanbeperformedwithlarge-scalemanual
210–2,860musclespindles/cm3inmuscletissuesinthe techniques.
backoftheBladder-Meridian[225].
MostacupointscontainingthistypeofNAUsare
Relativelydenseandconcentratedcutaneousreceptors locatedonthefingerpads,palms,plantarareas,andthe
Cutaneous-receptor- dominateinNAUs.About100–240encapsulated surroundingofthelips,forexample,Shao-Shang
rich cutaneousreceptors/mm2and300freenerve (LU11),Lao-Gong(PC12),andRen-Zhong(GV26).
NAUs endings/mm2aredistributedinthecutaneoustissuesof Onlyprickandshallowneedlingcangenerallybe
thefingerpads[226]. performedontheseacupoints.
MostacupointscontainingthistypeofNAUsare
Tendon-organ-rich Tendonorgans,RuffiniandPaciniancorpuscles locatedaroundtheelbow,wrist,knee,andanklejoints,
NAUs dominateinNAUs. forexample,Chi-Ze(LU5),Da-Ling(PC7),Du-Bi
(ST35),andJie-Xi(ST41).
10 Evidence-BasedComplementaryandAlternativeMedicine
Table3:TheputativerelationshipbetweenNAUpropertiesandneedlingsensation.
Componentsofneedlingsensation
NAUproperties
Aching/soreness/warmth Numbness/heaviness/distension
TypeofNAUs Cutaneous-receptor-richNAUswithapredominance Muscle-spindle-andtendon-organ-richNAUs.
ofnociceptors.
NAUreactions Biochemicalreaction Biophysicalreaction
Dominantafferent AδandC AβandAδ
fibers
Acupuncture Prick; shallow needling; high-frequency EA; laser Mostmanualtechniquesingentleandrepetitivemanip-
stimulationmodesa acupuncture;heatacupuncture. ulation;low-frequency,high-intensityEAandTENS.
aLow-frequency,high-intensityEAandTENSisthoughttodominantlyactivatesmyelinatedfibers(AβandAδ),whereashigh-frequencyEAmainlyactivate
small-diametermyelinatedAδfibersandunmyelinatedCfibers[133,134].
bEA,electroacupuncture;TENS,transcutaneouselectricalnervestimulation.
outcomes[75].Needlingsensationis,therefore,suggestedto pathway is involved in the transmission of NAU afferent
beapredictorforacupunctureanalgesia[76].Althoughthe impulses from the trigeminal territory [84]. Via these
perceptionofneedlingsensationmayvaryinindividualsand pathways, most NAU afferent signals are carried up to the
with manual techniques, this distinct sensation is generally brainstem,wherethesignalsarerelayedtoothersubcortical
characterized by soreness, numbness, heaviness, distension, andcorticalareasviadirectprojectionsandcollateralbranch
andachinginthedeeptissuessurroundingtheinsertednee- connections.MajorcentralneuralpathwaysprocessingNAU
dle[76],andoftenaccompaniesincreasedbloodflowwitha afferentimpulsesareillustratedinFigure6.
feeling of warmth at acupoint areas [77, 78]. The sensation
alsocanbetransmittedtotheacupuncturist’sfingers,which
7.1. The Spinal-Supraspinal Pathways. The spinal-suprasp-
feelincreasedresistancetofurthermovementoftheinserted
inal pathways responsible for transmitting NAU afferent
needle [79]. Thus, the needling sensation is not a single,
impulses from the territory innervated by the spinal nerves
but a compound sensation that is generated from the acti-
mainlycomprisethespinothalamictract,thespinoreticular
vation of various sensory receptors and their afferent fibers
tract, and the dorsal column-medial lemniscus tract. Most
in NAUs, in particular, small fiber-innervated nociceptors
peripheral small afferent fibers bearing “positive” noxious
and myelinated fiber-innervated mechanoreceptors, which,
signals from NAUs in the limbs, the trunk, and the neck
respectively, produce afferent impulses via biochemical and
terminate in the superficial layers of the spinal dorsal
biophysicalmechanismsofNAUsasdescribed.
horn, where the signals are relayed and carried up by the
It is also well demonstrated that numbness, heaviness,
contralateral spinothalamic tract to supraspinal levels [83].
and distension during needling are closely associated with
Most peripheral thick myelinated afferent fibers bearing
the activation of myelinated Aβ and Aδ afferents in deep
NAU mechanoreceptor-activated signals in the spinal nerve
issues of acupoints, whereas aching and soreness are highly
territory separately enter the ipsilateral dorsal column-
correlated with stimulation of small myelinated Aδ and
medial lemniscus tract and emerge into the contralat-
unmyelinated C fibers [10, 80–82]. Clinical practice also
eral spinothalamic tract. NAU impulses conveyed by the
suggeststhatnumbness,heaviness,anddistensionaremore
spinothalamic tract and the dorsal column are further
often elicited when manual manipulation is performed
relayed in the brainstem and the thalamus and ultimately
in muscle-spindle- and tendon-organ-rich NAUs, whereas
sent to the somatosensory cortex in a somatotopic fashion
the sensation evoked in cutaneous-receptor-rich NAUs is
[83].Paralleltothesomatotopicpathways,thespinoreticular
dominatedbyachingandsoreness.Theputativerelationship
tractreceivesNAUimpulseslargelyviacollateralconnections
betweenNAUpropertiesandcomponentsofneedlingsensa-
withthesomatotopicpathwaysatthespinalandsupraspinal
tionissummarizedinTable3.
levelsanddiffuselyprojectstosubcorticalandcorticalareas
[83].
7.MultipleCentralNeuralPathwaysConveying It is well documented that the spinothalamic and spin-
NAUAfferentImpulses oreticulartractsarethetwokeyascendingpathways,which
convey NAU “positive” tissue injury-evoked signals and
As described above, acupuncture-evoked afferent impulses activate the descending noxious inhibitory system [3, 83].
in most NAUs are mainly constituted by “positive” tis- Thelattermainlyconsistsoftheperiaqueductalgray(PAG)
sue injury-induced and mechanoreceptor-activated com- nucleus raphe magnus (NRM) spinal pathway and the
ponents. Neuroanatomically, there exist separate central locus coeruleus (LC)-spinal pathway. These send inhibitory
pathways processing NAU afferent impulses from different information to the spinal dorsal horn and block noxious
components and from different parts of the body. Several signal inputs from the periphery [3, 83, 85]. In addition to
spinal-supraspinal pathways responsible for acupuncture receivingsignalsfromtheascendingpathways,thedescend-
analgesiahavebeenidentified[3,83].Thetrigeminalsensory inginhibitorysystemalsoreceiveswideafferentmodulation