Acupuncture-Analgesia-Mediated Alleviation of Central ...downloads.hindawi.com/journals/ecam/2019/6173412.pdf · synaptic facilitation and engage central sensitization-like mechanisms

Review ArticleAcupuncture-Analgesia-Mediated Alleviation ofCentral Sensitization

Hsiang-Chun Lai 1 Yi-Wen Lin 234 and Ching-Liang Hsieh 1345

1Department of Chinese Medicine China Medical University Hospital Taichung 40447 Taiwan2Graduate Institute of Acupuncture Science College of Chinese Medicine China Medical University Taichung 40402 Taiwan3Chinese Medicine Research Center China Medical University Taichung 40402 Taiwan4Research Center for Chinese Medicine and Acupuncture China Medical University Taichung 40402 Taiwan5Graduate Institute of Integrated Medicine College of Chinese Medicine China Medical University Taichung 40402 Taiwan

Correspondence should be addressed to Ching-Liang Hsieh clhsiehmailcmuhorgtw

Received 23 April 2018 Revised 20 July 2018 Accepted 6 February 2019 Published 7 March 2019

Academic Editor Vitaly Napadow

Copyright copy 2019 Hsiang-Chun Lai et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Pain can trigger central amplification called central sensitization which ultimately results in hyperalgesia andor allodyniaMany reports have showed acupuncture has an analgesic effect We searched the related article on PubMed database andCochrane database to discover central sensitization pathway in acupuncture analgesia We summarized that acupunctureenhances the descending inhibitory effect and modulates the feeling of pain thus modifying central sensitization The possiblemechanisms underlying the analgesic effects of acupuncture include segmental inhibition and the activation of the endogenousopioid adrenergic 5-hydroxytryptamine and N-methyl-D-aspartic acid 120572-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacidkainate pathways Moreover acupuncture can locally reduce the levels of inflammatory mediators In clinical settingsacupuncture can be used to treat headache neuropathic pain low back pain osteoarthritis and irritable bowel syndrome Thesemechanisms of acupuncture analgesia may be involved in the alleviation of central sensitization

1 Introduction

Pain is one of themost common clinical problemsworldwideand it adversely affects quality of life The generation ofpain results from tissue damage or similar pathophysio-logical causes Signal transmission pathways of pain suchas the spinothalamic pathway involve multiple gates andinterfering effects to mislead the brain [1] In its viciouscycle a pain stimulus itself can trigger the central ampli-fication of pain called central sensitization and ultimatelycause hyperalgesia [2] Pain management includes strategiessuch as pharmacotherapy physical activity social supportacupuncture heating rest diets or lifestyle changes [3]Central sensitization is defined as ldquoan amplification of neuralsignaling within the central nervous system (CNS) that elicitspain hypersensitivityrdquo [4] Therefore central sensitizationis due to a nociceptive input that results in a persistentincrease in the excitability and synaptic effect of neurons in

the nociceptive pathways of the CNS and this phenomenonmaintains a persistent state of heightened reactivity [4]Central sensitization is due to an enhanced response ofthe CNS which causes the development of hyperalgesia[5] Altered membrane excitability reduced inhibitory trans-mission and increased synaptic efficacy contribute to thedevelopment of central sensitizationThe lamina I and laminaV neurons of the spinal cord as well as the thalamus amyg-dala and anterior cingulate cortex are involved in centralsensitization [6] Therefore central sensitization is due toa persistent state of high reactivity of nociceptive afferentneurons in the CNS The pathological changes followingtissue damage and nerve injury in the dorsal root ganglion(DRG) and dorsal horn of the spinal cord may create a stateof chronic pain and some of the mechanisms underlyingthis phenomenon are outlined as follows (1) alteration ofsodium and potassium ion channel expression in the DRG(2) release of glutamate from the primary afferent neurons

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2019 Article ID 6173412 13 pageshttpsdoiorg10115520196173412

2 Evidence-Based Complementary and Alternative Medicine

PubMed database 1766 articles

Cochrane database 6 articles

1772 articles

313 articles

170 articles

49 articles49 articles72 articles

Exclude 1459 articles1 No abstract2 Not related to acupuncture and

central sensitization in abstract

Exclude 143 articles1 Not available for full text2 Not related to acupuncture and

central sensitization in full text

ReviewClinical trialsBasic research

Figure 1 Flow chart of the search processes

and increase in glutamate receptor function in the second-order neurons as well as disinhibition of local inhibitory120574-aminobutyric acid (GABA)ergic and glycinergic interneu-rons in the dorsal horn of the spinal cord and (3) releaseof cytokines and chemokines caused by the activation ofspinal microglia and astrocytes [7] Hyperalgesia (increasedpain sensitivity) and allodynia (pain production induced by anonnociceptive stimulation) are the two main characteristicsof central sensitization [5] Many clinical syndromesmdashsuchas rheumatoid arthritis osteoarthritis temporomandibulardisorders fibromyalgia musculoskeletal disorders tension-type headache neuropathic pain complex regional painsyndrome and postsurgical painmdashmay contribute to centralsensitization [4]

Acupuncture is a well-known treatment modality thatoriginated in China This procedure includes the insertion ofneedles into specific points of the body (called acupoints) toachieve therapeutic effects According to the theory of tra-ditional Chinese medicine (TCM) acupuncture modulatesthe flow of Qi and blood through the meridians and restoresthe balance of the five organs to maintain homeostasis [8]To date acupuncture is considered a valid treatment methodfor alleviating acute and chronic pain in clinical practiceMany studies have discussed the possible mechanism of painreduction through acupuncture treatment

In this article we review the mechanisms of pain thecauses of central sensitization and the mechanisms under-lying acupuncture analgesia

2 Methods

We searched the PubMed database and Cochrane databasefor studies published unlimited beginning date to November2017 The keywords included ldquoacupuncturerdquo ldquopathophysiol-ogyrdquo ldquocentral sensitizationrdquo ldquoanalgesiardquo and ldquopainrdquo Lan-guage was limited to English and Chinese The filter processwas firstly by search engine of the website which yielded 1772articles We excluded 1459 articles due to no abstract or not

related to acupuncture and central sensitization in abstractby the authors which yielded 313 articles We excluded 143articles due to no full text or not related to acupunctureand central sensitization in full text by the authors whichyielded 170 articles Therefore the basic clinical and reviewarticle were 72 49 and 49 respectively in type of articleThe manuscript included basic and clinical studies related tocentral sensitization and acupuncture analgesia Flow chart ofthe search processes was as shown in Figure 1

21 Physiology of Pain Somatic sensations are relays fromthe peripheral receptors to the brain cortex Signals aretransferred from distal nociceptors to the dorsal horn ofthe spinal cord (synapsing on second-order neurons) andthrough the brainstem to the ventral posterolateral nucleus ofthe thalamus Finally the signals are projected to the postcen-tral gyrus of the parietal cortex The ascending transductionis called the lateral spinothalamic pathway or anterolateralsystem [9ndash11]

The descending modulatory pathway plays a crucial rolein acupuncture analgesia The pathway includes the cortexventrolateral (vl) periaqueductal gray (PAG vlPAG) matterrostral ventromedial medulla (RVM) locus coeruleus raphenucleus and inhibitory synapses in the dorsal horn of thespinal cord [12]

22 Mechanism of Pain-Induced Central Sensitization Thesensory processing of pain is similar to a neural relay fromthe distinct pain-affected region of the body to the braincortex The upregulation or downregulation of each gatewould interfere with the ldquofeelingrdquo of ordinary sensationsThe threshold for activating primary afferent nociceptorsis reduced under intense repeated or prolonged stimuliThe relatively low threshold of the nerve ending contributesto a relatively high frequency of firing for stimuli of allintensities Central sensitization occurs with inflammatorymediators such as bradykinin nerve-growth factor someprostaglandins leukotrienes and nitric oxide [13] After

Evidence-Based Complementary and Alternative Medicine 3

GlutamateAdenosine

BDNF

Repeat stimuli Intense stimuli

Prolonged stimuli

NeuroplasticityLearning


Limbic system

Inflammation substance

Dorsal horn of spinal cord

Glutamate Substance P prostaglandins NO NMDA-R

PAG RVMOpioid system Adrenergic system 5-HT BDNF

Central sensitizationCortex

Nerve ending Receptor

Figure 2Mechanisms of pain-induced central sensitization Pain transduction pathway (hollow arrows) upregulation of central sensitization(solid broad arrows) downregulation of central sensitization (solid thin arrows) 5-HT 5-hydroxytryptamine BDNF brain-derivedneurotrophic factor NDMA N-methyl-D-aspartic acid NO nitric oxide PAG periaqueductal gray RVM rostral ventromedial medulla

central sensitization light stimuli can also produce pain thiscondition is called allodynia

In the dorsal horn of the spinal cord the nociceptivenerve endings release glutamate and substance P whichact as postsynaptic N-methyl-D-aspartate (NMDA) andneurokinin-1 receptors during neural central sensitizationThis mechanism prolongs the painful state [11] In acuteperipheral nerve injury the loss of 120574-aminobutyric acid(GABA)ergic interneurons reduces inhibitory control andincreases the firing of the dorsal horn neurons [14] Glia andimmunocompetent cells in the dorsal horn secrete glutamatecytokines neurotrophins nitric oxide prostaglandins andadenosine 51015840-triphosphate These elements can amplify thepain pathway [15] Repeated stimuli were reported to increasethe expression of ionizing calcium-binding adapter molecule1 and cause microglial hypertrophy in an animal model [16]

Brain-derived neurotrophic factor (BDNF) has beenidentified as a critical regulator of neuronal developmentsynaptic transmission and synaptic plasticity BDNF can acton the dorsal horn neurons of the spinal cord and increasetheir excitability and spinal long-term potentiation in addi-tion to inducing inflammatory pain [17] It can enhancesynaptic facilitation and engage central sensitization-likemechanisms [18] BDNF-containing neurons have beenobserved in PAG and RVM Upregulation of tropomyosinreceptor kinase B (TrkB) a BDNF receptor after inflamma-tion aggravates descending pain facilitation [19]

NMDA receptor (NMDAR) activation increases painsensitivity of the spinal cord and brain [20 21] The mainbinding ligands are glutamate and glycine (or d-serine)Increased glutamate levels in the posterior cingulate gyrusposterior insula prefrontal cortex and amygdalawould causedysregulation of pain processing in the central nervous

system (CNS) [22] Recently BDNF was found to share thesame downstream activator as NMDARs TrkB signalingThe hypothesis was that both BDNF and other NMDARligands contribute to the hyperalgesia in the brain andthe maintenance of spinal long-term potentiation dependsmainly on self-regenerating glial BDNF [23 24]

In the CNS enkephalins and endorphins bind to 120583-opioid receptors inhibit the release of substance P andreduce the pain sensation This effect was observed duringmesencephalic reticular formation in the amygdala PAGmatter and RVM [25] In the human brain pain can causestructural changes in gray and white matter These changesenable people to learn new skills and build behaviors Italso engenders the process of ldquolearning chronic painrdquo Ina previous study structural plasticity and glial hypertrophywere observed in the hippocampus and the subventricularzone [26]

Central sensitization can also be exaggerated and main-tained because of cognition attention emotions and moti-vation [27] These factors can modify experiences of painA summary of the mechanisms of pain-induced centralsensitization is presented in Figure 2

23 Possible Mechanisms of Central SensitizationReduction through Acupuncture Analgesia

231 Segmental Inhibition or Gate Controleory A synapsein the dorsal horn of the spinal cord with a nociceptivenerve ending releases a neurotransmitter which acts onpostsynaptic receptors during neural central sensitizationThe impulse of pain sensation is proportional to the numberof sensitive loci and sensitized nociceptors involved If thesesensitized nociceptors send massive neural impulses to the


spinal cord it amplifies the central sensitization of exactlythe same segments of the dorsal horn cells that govern azone of pain referral [28 29] In the segment of needling thepressure pain threshold increases which indicates segmentalinhibition in the spinal cord [30] The segmental modulatingmechanisms play a critical role in acupuncture analgesiawhich has been reported in a double-blind randomizedcontrolled trial in patients with myofascial pain [31]

232 Endogenous Opioid Pathway The most well-knownmechanism of acupuncture analgesia is the endogenousopioid pathway [32] In experiments conducted on animalmodels we have found that different frequencies of elec-troacupuncture (EA) caused different types of endogenousanalgesia release an EA treatment of 2 Hz accelerated therelease of enkephalin beta-endorphin and endomorphinand an EA treatment of 100 Hz increased the release ofdynorphin [33ndash35] Combining high and low frequencies canstimulate the release of four opioid peptides and providethe maximal therapeutic effect [34] This analgesic processcan be reversed by administering low doses of the opioidantagonist naloxone [36] and an antibody against encephalinor dynorphin [33] We have concluded that the EA stimu-lation and opioid peptides share a common pathway in theCNS Niddam et al revealed that relieving pain through EAstimulation on a trigger point was mediated through thecentral pain modulation of the PAG in the brainstem [37]Changes in PAG opioid activity were hypothesized to occurdue to needling needling may stimulate the nociceptivefibers thus activating the enkephalinergic inhibitory dorsalhorn interneurons [38]

The neuropeptide nociceptinorphanin FQ (NOFQ) isthe endogenous agonist of theNOFQpeptide receptor (NOPreceptor) It was determined to have many physiological andpathological functions in pain regulation [39] NOP receptorsare found in the nucleus raphe magnus (NRM) dorsal raphenucleus and vlPAG [8 40] Fu et al have reported that thelevels of the precursor protein for NOFQ increased andthe NOFQ immune reactivity decreased after peripheralinflammation in the superficial layers of the spinal dorsalhorn [39 41]This process significantly increases after chronicinflammatory pain however it can be alleviated through EAtreatment and warming moxibustion [42]

233 Adrenergic Pathway Norepinephrine is a potentinducer of analgesia in the spinal cord In the descendingpain modulation pathway noradrenaline (norepinephrine)-containing neurons can be found in the raphe nuclei locuscoeruleus PAG matter and A1 A2 and A4-7 nuclei of thebrainstem These neurons project into the forebrain andpass through the dorsolateral tracts of the spinal cord [43]Multiple animal studies have reported that acupuncture canreduce allodynia through the activation of an adrenergicmechanism [44ndash53] Alpha2- and beta-adrenoceptors havebeen the most frequently reported receptors [46 47 51ndash53]Chen et al reported that alpha 2C receptors inhibit the releaseof opioids in the dorsal horn Consequently the activationof the adrenergic system can shut down the opioid system inthe dorsal horn of the spinal cord segmentation [54]

234 5-Hydroxytryptamine Pathway Serotoninergic neu-rons are found in the NRM RVM and trigeminal nucleuscaudalis (TNC) and they project into the spinal cord [38] Inan inflammatory pain rat model EA analgesia was mediatedby a 5-hydroxytryptamine (5-HT) neurotransmitter whichbinds to 5-HT1 and 5-HT3 receptors [55 56]This process canbe reversed by 5-HT1 and 5-HT3 antagonists Headache reliefwas considered to be primarily engendered by an increase inserotonin release in the medulla and TNC regions [57 58]Serotonin could inhibit inflammatory and neuropathic painmore effectively at 2ndash10Hz than at 100Hz [59] Another studyreported 5-HT1A and 5-HT3 receptors partially mediated theanalgesic effects of EA at 2ndash10 Hz By contrast the 5-HT2receptor was conversely involved in the nociceptive responseat 100 Hz [60]

235 NDMA120572-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepro-pionic AcidKainate Pathway Glutamate and aspartate areexcitatory amino acids which bind to the NMDA120572-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)kainate (KA) pathway and metabotropic receptors inthe dorsal horn of spinal cord fiber terminals [61] Afterprolonged and intense nociceptive impulse substance Preleased in the dorsal horn increased the responsivenessof the NMDAR to glutamate and enhanced the spreadof noxious input This process also results in presynapticmodulation of astroglia which contributed to central painsensitization [62]

Several animal studies have shown that EA treatment canattenuate the hyperalgesia of neuropathic pain through thedownregulation of NMDAR phosphorylation at the spinalcord level [63ndash66] EA decreases in the expression level of theNR-2B subunit of theNMDAR in the dorsal horn [51 67ndash69]Huang et al revealed that combining low-dose ketamine anNMDAR antagonist with EA produced antiallodynic effectsof a higher magnitude than did EA alone in a neuropathicpain model This process could be reversed by naloxonewhich indicates the possible interaction between the NMDAand endogenous opioid systems [64] Gao et al reported thatEA at ST-36 causes the upregulation of NMDAR-mediatedsynaptic transmission and enhancement of gastric motilitywhich can alleviate irritable bowel symptoms [70]

236 Local Inflammatory Environment Local environmentof active trigger zone is characterized by considerably higherlevels of substance P calcitonin gene-related peptide (CGRP)bradykinin (BK) 5-HT norepinephrine tumor necrosisfactor-120572 (TNF-120572) and interleukin-1120573 (IL-1120573) compared withnormal muscle tissue [71 72] These chemicals sensitizeand activate muscle nociceptors transfer impulse to thebrain and recruit spinal microglial cells for an inflam-matory response in the microenvironment [73 74] Theinflammation process causes neuronal hyperexcitability andamplifies nociception resulting in chronic and neuropathicpain Clinical improvement is accompanied by a reduction inthe levels of inflammatory substances such as IL-1120573 IL-8 IL-10 and TNF-120572 [8] Administration of EA on GB-30 increaseslocal CndashXndashC motif chemokine 10 (CXCL 10) production and


Table 1 Possible pathways through which acupuncture analgesia alleviates central sensitization

Mechanism Related part of neuronnucleus(1) Segmental inhibition dorsal horn(2) Endogenous opioid pathway dorsal horn PAG NRM dorsal raphe nucleus(3) Adrenergic pathway dorsal horn PAG raphe nuclei locus coeruleus and brainstem (A1 A2 A4-7 nuclei) forebrain(4) 5-Hydroxytryptamine pathway NRM RVM trigeminal nucleus caudalis(5) NDMA pathway dorsal horn(6) Local inflammatory environment nerve ending dorsal hornNMDA N-methyl-D-aspartic acid PAG periaqueductal gray NRM nucleus raphe magnus RVM rostral ventromedial medulla

activates the peripheral opioid peptidendashmediated antinoci-ception process [75] thus suggesting that acupuncture cancause an interaction between local opioid receptors andthe mediators of anti-inflammatory responses In additionthe possible pathways underlying the acupuncture-analgesia-mediated reduction in central sensitization are summarizedin Table 1

24 Acupuncture Analgesia Related to Central Sensitization

241 Headache (Tension-Type Headache Migraine and Clus-ter Headache) Headache is described using characteristicssuch as throbbing dullness tightness or pressure in thehead It is primarily diagnosed as migraines tension-typeheadaches cluster headaches or other secondary causes [76]A headache is generally induced by tau band stress or thelocal release of inflammatory substances and it is conductedvia C fibers and A120575 nociceptive neurons to the dorsal hornand trigeminal nucleus in the trigeminocervical complexsynapsing to the second-order neurons [77] In the case of fre-quent and high intensity stimuli these neurons are recruitedvia homosynaptic andheterosynaptic facilitationwhich leadsto the release of neuropeptides and neurotransmitters includ-ing NMDA cyclooxygenase-2 (COX-2) nitric oxide and fos[78ndash80] A study on rats revealed that elevated levels of BDNFa neuroplasticitymediator in cerebrospinal fluid (CSF) resultin synaptic plasticity [81] The generated synaptic plasticityand accumulation of neurotransmitters such as substanceP and glutamate can cause inefficiency diffused noxiousinhibitory control and persistent sensitization thus reducingpain thresholds and contributing to central sensitization ofheadache [80 82]

(1) Tension-Type Headache Patients with tension-typeheadache were found to have reduced pressure paindetection and tolerance thresholds in the temporal regioncompared with the controls [83] The qualitative alteration innociception was caused by central sensitization at the triggerpoint hyperalgesic zone and the level of the spinal dorsalhorn and trigeminal nucleus [84 85] EA was demonstratedto block this pathway and inhibit neuroplasticity by reducingthe BDNF level in a 29-participant human study [86]

(2) Migraine The central sensitization pathophysiology of amigraine originates from persistent cutaneous hypersensitiv-ity and general neuronal hyperexcitability and leads to RVMcentral sensitization [87] Cutaneous allodynia is observed in

migraine [88] Boyer et al demonstrated that repeated duralstimulation potentiates touch-induced fos expression in thetrigeminal and spinal dorsal horns and causes diffuse noxiousinhibitory control impairment and widespread trigeminaland spinal central sensitization [82]

In a randomized controlled trial involving 275 patientswith migraine EA on GB-40 was found to cause a significantdifference in the visual analgesic scale scores of the EAand control groups This effect of EA was accompanied byelevated 5-HT levels in the EA group [89] EA also inducedupregulation of cannabinoid receptor type 1 (CB1) resultingin the inhibition of the inflammatory effects of IL-1120573 COX-2Prostaglandin E2 and CGRP in a migraine rat model [90]

(3) Cluster Headache Cluster headache is a relatively raretype of primary headache but probably the most disablingand painful type [91]The possible pathophysiology of clusterheadache is associated with central sensitization of thebrainstem and possibly thalamic neurons [92] Fernandezet al observed widespread pressure pain hypersensitivityin patients with cluster headache compared with healthycontrols [93] In addition cluster headache patients wereobserved having decreasing plasma methionine-enkephalinlevels [94] However lower CSF met-enkephalin levels inpatients with cluster headache can be increased by manualacupuncture or EA [95]

In summary acupuncture treats headache through theinhibition of neuropeptide (substance P) neurotransmitters(glutamate) and BDNF as well as the release of opioidsubstances

242 Neuropathic Pain Allodynia and hyperalgesia arecommon symptoms in patients with neuropathic pain Theprevalence of chronic pain with neuropathic characteristicswas reported to range from 3 to 17 [96]

The origin of neuropathic pain is the input of terminal Cfibers and A120573 fibers which transfer signals to second-orderprojection neurons in the spinal cord C fiber overactiva-tion by capsaicin amplification in the spinal cord signalingsystems causes central sensitization [97] Landerholm et alfound that the modality of the evoked sensation changedfrom dynamic mechanical allodynia to dynamic mechanicaldysesthesia after gradually increasing the compression blockof A120573 input This finding indicates that A120573 input is crucialto the presence of allodynia and is part of the spectrum ofdysesthesia [98] After nerve injury second-order neuronsare excited by increased input from the healthy area and


nonnoxious input from damaged or undamaged A120573 fiberswhich cause central sensitization Both types of repetitivestimuli may cause pain Acupuncture attenuates nociceptivebehavior and reduces mechanical allodynia by activating thecomponents of the local molecular signaling pathway mainlyextracellular-signal-regulated kinase (ERK) [99] This effectexplains why acupuncture can be widely used for treatingneuropathic pain Additionally a change in the balance ofdescending inhibitory and activating pathways from the brainto the spinal cord modulates dorsal horn neuronal activityand causes analgesic effect through central sensitization[97]

From a molecular viewpoint allodynia has been deter-mined to be accompanied by elevation of neuropeptidessuch as CGRP substance P and the neurotrophin BDNFin A120573 fibers [100 101] Animal studies have also revealedthat acupuncture causes a reduction in glycine inhibition[102] and an increase in the activity of the neurotrophinBDNF (causing neuron plasticity) [101] NMDA AMPAand metabotropic glutamate receptors in the postsynapticneurons [103] Acupuncture increases the levels of theseneuropeptides including opioids serotonin norepinephrineand amino acids and reduces the levels of the local inflam-matory cytokines and the expression of their receptors [5963] In a neuropathic pain rat model repeated EA had atime-dependent cumulative analgesic effect this might beassociated with its modulatory effects on NK cells as well ason splenic IL-2120573 -Endorphin (120573-EP) and plasma IL-2 IL-1120573interferon gamma (IFN-120574) and transforming growth factorbeta (TGF-120573) levels [104] Many reports found that acupunc-ture can relieve neuropathic pain induced by postherpeticmultiple sclerosis cancer and anticancer treatment etc inhumans [105ndash108]

(1) Postherpetic NeuralgiaPostherpetic neuralgia (PHN) painis characterized by a deep burning and throbbing ache aswell as a sharp stabbing shooting lancinating pain [109]Theprevalence of PHN-associated neuropathic painwas reportedto be 39ndash420 per 100000 person-years [96] Allodynia wasobserved in at least 70 of patients with PHNThe identifiedrisk factors for PHN include advancing age high levelsof acute pain severe rashes prodromal pain ophthalmiclocation and possibly female sex [110] Although PHN isa vexing symptom only a few systemic studies have beenconducted on the use of acupuncture for the treatment of thiscondition

In animal studies EA was shown to alleviate PHNthrough recovering transient receptor potential vanilloidtype-1 (TRPV1)-positive sensory neurons [111] and reducingcerebral TRPV-4 expression [112] Regarding human studiesa single-blind randomized controlled study of acupuncturecompared with placebo was conducted on 62 patients withPHN the results suggested that acupuncture is effective intreating PHN [108] Lui et al recommended methods forselecting Ashi points and Huatuojiaji points to treat PHN[113]

(2) Trigeminal NeuralgiaThe prevalence of neuropathic painassociated with trigeminal neuralgia (TN) was revealed to be

126ndash289 per 100000 person-years [96] Patients experiencedintense paroxysmal pain and described it as being similarto an electric shock sensation (ldquopainful flashrdquo) that lastsapproximately 1 second and may recur within minutes Thispain is always unilateral and typically limited to the secondor third branch of the trigeminal nerve A trigger zone mayoccasionally exist which could cause an episode of pain aftertouching or stretching [114] Acupuncture can significantlyincrease the levels of plasma szlig-endorphin and szlig-lipotropinin patients with TN [115]

(3) Diabetic Peripheral NeuropathyTheprevalence of diabeticperipheral neuropathy (DPN)-associated neuropathic painwas shown to be 153ndash723 per 100000 person-years [96]Diabetic neuropathy affects up to 50 of patients withdiabetes for 25 years and painful DPN occurs in 264 ofall people with diabetes [116] The degree of pain rangesfrom mild dysesthesias to severe unremitting pain thatconsiderably hinders the patientsrsquo lives [117] Studies on DPNhave reported increased glutamate release from the primaryafferent neurons and reduced function of the presynapticGABAB receptors in the dorsal horn of the spinal cord[118 119] Spinal NMDAR overexpression frequently excitesthe postsynaptic lamina II neurons Moreover augmentedNMDA expression and glutamate release might contributeto spinal cord hyperactivity [120] The activation of GABABreceptors reduction inNMDAR expression in the spinal corddorsal horn [121] and increase in norepinephrine and 5-HTlevels in the spinal cord as well as RVM neurons were notedin DPN rats [122] These facilitation pathways account forcentral sensitization in diabetic neuropathy Consequentlyacupuncture provides an effective treatment [123]

Several one-arm studies have reported acupuncture to bea safe and effective therapy for painful diabetic neuropathy[124ndash126] The mechanisms underlying the analgesic effectsof acupuncture might be mediated by the inhibition of theNF-120581B signaling pathway in primary sensory neurons andsubstance P as seen in rat models [127 128] At the spinalcord level EA can increase the glutamic acid decarboxylase-67 (GAD-67) level reduce the TRPV-1 level and modulatethe nerve-growth factor level in rat models [128]

In summary the mechanisms though which acupuncturealleviates neuralgia mainly involve the enhancement of thedescending inhibition pathway including the release of opi-oids and the inhibition of NMDA In addition the inhibitionof local inflammation and TRPV1 receptors play a role in thealleviation of neuralgia

(4) Central Poststroke Pain Patients with central poststrokepain (CPSP) experience a continuous or paroxysmal painwhich was described in a previous study as burning achingpricking squeezing or throbbing either in isolation or invarious combinations of the aforementioned descriptions[129] The pain becomes severe after any stimuli such asmovement touch temperature or stress Allodynia dyses-thesia and hyperalgesia affect 33ndash86 of patients withCPSP [130] CPSP mostly develops on the contralateral sideto the stroke within 6 months of stroke onset and itsincidence decreases with time [131] The most common pain


is poststroke shoulder pain which occurs on the affected sideafter 2 to 3 months [132 133]

The mechanism of CPSP has been attributed to disinhi-bition theory implying the imbalance of stimuli and con-tribution to central sensitization [134] chronic nociceptive[135 136] or neuropathic pain [137ndash139] Lateral thalamusdysfunction frees the medial thalamus Then the spinotha-lamocortical pathway becomes prominently overactive inthe lateral thalamus and causes allodynia or dysaesthesia[129] Localized neurogenic inflammation induces the ini-tial phases of complex regional pain syndrome causingrepeated stimulation of the C fibers and increased medullaryexcitability (central sensitization) [140] Frequent stimulicontribute to the CNS plasticity and consolidation of allo-dyniadysaesthesia [141] In a functional magnetic resonanceimaging survey acupuncture stimulation was shown toactivate the limbic system including the parahippocampalgyrus and anterior cingulate cortex thus causing a centralanalgesic effect This result may provide a clue regarding theanalgesicmechanism of acupuncture [142] Salom-Moreno etal demonstrated that pain thresholds increased bilaterally inpatients receiving needling comparedwith thosewhodid not[143]

243 Low Back Pain (LBP) Low back pain has etiologyincluding muscles nerves and bones of the back Patientswould suffer from pain limited physical activity and sleepinterference Analgesics can provide temporary pain reliefbut have intolerable adverse effects for some patientsThus alternative treatments such as acupuncture [144] EAtranscutaneous electrical nerve stimulation (TENS) spinemanipulation and exercise therapy were options for thesepatients

Patients with LBP have lower pressure pain thresholdthan healthy individuals suggesting sensitization of the cen-tral nervous system [145]This effectmight be due to segmen-tal hyperresponsiveness hyperalgesia (thermal stimuli) andenhanced temporal summation compared to healthy groupwhich altered central nociceptive processing and causedchronic pain status [146] Lam demonstrates in a systematicreview that acupuncture has benefit in self-reported painand functional limitations [147] Another meta-analysis ofrandomized controlled trials suggests heat-sensitive moxi-bustion and acupuncture can improve lumbar disc herniation[148] This result was correlated to widespread oscillatorychanges in electroencephalography [149]

244 Osteoarthritis Joint Pain Osteoarthritis can beobserved as breakdown of joint cartilage and underlyingbone causing joint pain swelling decreased range ofmotion and daily activities limitations Treatment includeslifestyle change medication surgery and alternativetreatments Acupuncture served as an option to preventthe degeneration of cartilage [150] and pain relief [151]The central sensitization mechanism of osteoarthritisincludes disturbance in nociceptive processes local andwidespread hyperalgesia enhanced temporal or spatialsummation dysfunction of opioid and nonopioid system

and disturbance of proinflammatory cytokines neuropeptide[152]

EA attenuates the osteoarthritic pain by opioidergicreceptors 5-HT1 5-HT3 receptor andmuscarinic cholinergicreceptors [55 153 154] EA triggers chemokine CXCL10 toincrease opioid-containing macrophages and reduce inflam-matory pain [75] Moxibustion relieves osteoarthritic painalso mediated by endogenous opioids pathways [155]

245 Irritable Bowel Syndrome (IBS) IBS patients sufferedfrom recurrent abdominal pain and changes in the patternof bowel movements without organic disease It might betriggered by infection intestinal bacterial overgrowth stressfood sensitivity gastrointestinal motility visceral hypersen-sitivity and brain-gut axis problems Studies revealed IBSpatients were more sensitive to pain which related to centraldysfunction of viscerosomatic pathway [156 157]

Acupuncture relieves IBS symptoms in many reports[158ndash161] This effect was mediated by regulation of visceralhypersensitivity [162 163] EA decreases substance P in colonof rats [164 165] and modulates brain-gut axis throughdecreasing 5-HT CGRP CRF somatostatin and NMDAR-1and increasing NPY [166ndash170]

3 Conclusion

Acupuncture is a process that entails inserting needles intoacupoints triggering largemyelinated A120573- and A120575-fibers andtransducing a neural signal to postcentral gyrus of the parietalcortex The descending pathway passes through the raphenucleus locus coeruleus PAG prefrontal cortex insulacingulate cortex caudate nucleus amygdala and inhibitorysynapse in the dorsal horn The descending pathway mod-ulates the feeling of pain which interferes with the centralsensitization process

The possible mechanisms through which acupuncturereduces central sensitization include segmental inhibitionthe release of the endogenous opioid adrenergic and 5-HT and NMDAAMPAKA pathways The local effects ofacupuncture involve the reduction in the levels of inflam-matory mediators such as substance P IL-1120573 IL-8 IL-10and TNF-120572 In summary acupuncture acts through multiplepathways to produce analgesic effects and reduce centralsensitization Therefore acupuncture is beneficial for thetreatment of headache neuropathic pain low back painosteoarthritis and irritable bowel syndrome

Conflicts of Interest

We declare no conflicts of interest associated with thismanuscript

Authorsrsquo Contributions

H-C Lai collected data and wrote the manuscript Y-W Linparticipated in discussions and provided suggestions andC-L Hsieh provided an informed opinion and revised themanuscript


Acknowledgments

This work was financially supported by the ldquoChineseMedicine Research Center China Medical Universityrdquo fromthe Featured Areas Research Center Program within theframework of the Higher Education Sprout Project by theMinistry of Education (MOE) in Taiwan

References

[1] L J Crofford ldquoChronic pain Where the body meets thebrainrdquo Transactions of the American Clinical and ClimatologicalAssociation vol 126 pp 167ndash183 2015

[2] C J Woolf ldquoPain Moving from symptom control towardmechanism-specific pharmacologic managementrdquo Annals ofInternal Medicine vol 140 no 6 pp 441ndash451 2004

[3] Y Takai N Yamamoto-Mitani Y Abe and M Suzuki ldquoLitera-ture review of pain management for people with chronic painrdquoJapan Journal of Nursing Science vol 12 no 3 pp 167ndash183 2015

[4] C J Woolf ldquoCentral sensitization Implications for the diagno-sis and treatment of painrdquo Pain vol 152 no 3 pp S2ndashS15 2011

[5] J Sandkuhler ldquoModels and mechanisms of hyperalgesia andallodyniardquo Physiological Reviews vol 89 no 2 pp 707ndash7582009

[6] A Latremoliere and C J Woolf ldquoCentral sensitization Agenerator of pain hypersensitivity by central neural plasticityrdquoe Journal of Pain vol 10 no 9 pp 895ndash926 2009

[7] Q Xu and T L Yaksh ldquoA brief comparison of the pathophysiol-ogy of inflammatory versus neuropathic painrdquoCurrent Opinionin Anaesthesiology vol 24 no 4 pp 400ndash407 2011

[8] L Leung ldquoNeurophysiological basis of acupuncture-inducedanalgesiamdashan updated reviewrdquo Journal of Acupuncture andMeridian Studies vol 5 no 6 pp 261ndash270 2012

[9] A I Basbaum D M Bautista G Scherrer and D JuliusldquoCellular and molecular mechanisms of painrdquo Cell vol 139 no2 pp 267ndash284 2009

[10] A E Dubin and A Patapoutian ldquoNociceptors The sensors ofthe pain pathwayrdquoe Journal of Clinical Investigation vol 120no 11 pp 3760ndash3772 2010

[11] M J Millan ldquoThe induction of pain An integrative reviewrdquoProgress in Neurobiology vol 57 no 1 pp 1ndash164 1999

[12] I C Umana C A Daniele B A Miller et al ldquoNicotinicmodulation of descending pain control circuitryrdquo Pain vol 158no 10 pp 1938ndash1950 2017

[13] G D Iannetti L Zambreanu R G Wise et al ldquoPharmaco-logical modulation of pain-related brain activity during normaland central sensitization states in humansrdquo Proceedings of theNational Acadamy of Sciences of the United States of Americavol 102 no 50 pp 18195ndash18200 2005

[14] S E Ross A R Mardinly A E McCord et al ldquoLoss ofinhibitory interneurons in the dorsal spinal cord and elevateditch in Bhlhb5mutantmicerdquoNeuron vol 65 no 6 pp 886ndash8982010

[15] A Vernadakis ldquoGlia-neuron intercommunications and synap-tic plasticityrdquo Progress in Neurobiology vol 49 no 3 pp 185ndash214 1996

[16] F Y Zheng W-H Xiao and G J Bennett ldquoThe response ofspinal microglia to chemotherapy-evoked painful peripheralneuropathies is distinct from that evoked by traumatic nerveinjuriesrdquo Neuroscience vol 176 pp 447ndash454 2011

[17] X-H Cao S-R Chen L Li and H-L Pan ldquoNerve injuryincreases brain-derived neurotrophic factor levels to suppressBK channel activity in primary sensory neuronsrdquo Journal ofNeurochemistry vol 121 no 6 pp 944ndash953 2012

[18] S M Garraway and J R Huie ldquoSpinal plasticity and behaviorBDNF-induced neuromodulation in uninjured and injuredspinal cordrdquo Neural Plasticity vol 2016 Article ID 98572012016

[19] W Guo M T Robbins F Wei et al ldquoSupraspinal brain-derived neurotrophic factor signaling A novel mechanism fordescending pain facilitationrdquo e Journal of Neuroscience vol26 no 1 pp 126ndash137 2006

[20] G Littlejohn and E Guymer ldquoModulation of NMDA receptoractivity in fibromyalgiardquo Biomedicines vol 5 no 2 2017

[21] K Bannister M Kucharczyk and A H Dickenson ldquoHopes forthe future of pain controlrdquo Pain and erapy vol 6 no 2 pp117ndash128 2017

[22] T L Pyke P G Osmotherly and S Baines ldquoMeasuring gluta-mate levels in the brains of fibromyalgia patients and a potentialrole for glutamate in the pathophysiology of fibromyalgiasymptoms A systematic reviewrdquo e Clinical Journal of Painvol 33 no 10 pp 944ndash954 2017

[23] J L Marcos D Galleguillos T Pelissier et al ldquoRole of thespinal TrkB-NMDA receptor link in the BDNF-induced long-lastingmechanical hyperalgesia in the rat A behavioural studyrdquoEuropean Journal of Pain vol 21 no 10 pp 1688ndash1696 2017

[24] S Li J Cai Z-B Feng et al ldquoBDNF contributes to spinallong-term potentiation and mechanical hypersensitivity viafyn-mediated phosphorylation of NMDA receptor GLUN2Bsubunit at tyrosine 1472 in rats following spinal nerve ligationrdquoNeurochemical Research vol 42 no 10 pp 2712ndash2729 2017

[25] A S Sprouse-Blum G Smith D Sugai and F D ParsaldquoUnderstanding endorphins and their importance in painmanagementrdquo Hawaii Medical Journal vol 69 no 3 pp 70-712010

[26] G Rusanescu and JMao ldquoPeripheral nerve injury induces adultbrain neurogenesis and remodellingrdquo Journal of Cellular andMolecular Medicine vol 21 no 2 pp 299ndash314 2017

[27] J F Brosschot ldquoCognitive-emotional sensitization and somatichealth complaintsrdquo Scandinavian Journal of Psychology vol 43no 2 pp 113ndash121 2002

[28] Y-L Hsieh M-J Kao T-S Kuan S-M Chen et al ldquoDryneedling to a key myofascial trigger point may reduce theirritability of satellite MTrPsrdquo American Journal of PhysicalMedicine amp Rehabilitation vol 86 no 5 pp 397ndash403 2007

[29] Y-L Hsieh L-W Chou Y-S Joe and C-Z Hong ldquoSpinal cordmechanism involving the remote effects of dry needling on theirritability of myofascial trigger spots in rabbit skeletal musclerdquoArchives of Physical Medicine amp Rehabilitation vol 92 no 7 pp1098ndash1105 2011

[30] P I Baeumler J Fleckenstein F Benedikt J Bader andD Irnich ldquoAcupuncture-induced changes of pressure painthreshold are mediated by segmental inhibition - a randomizedcontrolled trialrdquo Pain vol 156 no 11 pp 2245ndash2255 2015

[31] J Z Srbely J P Dickey D Lee and M Lowerison ldquoDry needlestimulation of myofascial trigger points evokes segmental anti-nociceptive effectsrdquo Journal of Rehabilitation Medicine vol 42no 5 pp 463ndash468 2010

[32] L W Chou M J Kao and J G Lin ldquoProbable mechanisms ofneedling therapies for myofascial pain controlrdquo Evidence BasedComplementary and Alternative Medicine vol 2012 Article ID705327 11 pages 2012


[33] J S Han ldquoAcupuncture Neuropeptide release produced byelectrical stimulation of different frequenciesrdquo Trends in Neu-rosciences vol 26 no 1 pp 17ndash22 2003

[34] J-S Han ldquoAcupuncture and endorphinsrdquo Neuroscience Lettersvol 361 no 1ndash3 pp 258ndash261 2004

[35] D Mayor ldquoAn exploratory review of the electroacupunctureliterature Clinical applications and endorphin mechanismsrdquoAcupuncture in Medicine vol 31 no 4 pp 409ndash415 2013

[36] R S S Cheng and B Pomeranz ldquoElectroacupuncture analgesiacould be mediated by at least two pain-relieving mechanismsendorphin and non-endorphin systemsrdquo Life Sciences vol 25no 23 pp 1957ndash1962 1979

[37] DMNiddamR-C Chan S-H Lee T-C Yeh and J-CHsiehldquoCentral modulation of pain evoked from myofascial triggerpointrdquoe Clinical Journal of Pain vol 23 no 5 pp 440ndash4482007

[38] B Cagnie V Dewitte T Barbe F Timmermans N Delrue andM Meeus ldquoPhysiologic effects of dry needlingrdquo Current Painand Headache Reports vol 17 no 8 article no 348 2013

[39] X Fu Y-Q Wang and G-C Wu ldquoInvolvement of noci-ceptinorphanin FQ and its receptor in electroacupuncture-produced anti-hyperalgesia in rats with peripheral inflamma-tionrdquo Brain Research vol 1078 no 1 pp 212ndash218 2006

[40] F Ma H Xie Z-Q Dong Y-Q Wang and G-C Wu ldquoEffectsof electroacupuncture on orphanin FQ immunoreactivity andpreproorphanin FQ mRNA in nucleus of raphe magnus in theneuropathic pain ratsrdquoBrain Research Bulletin vol 63 no 6 pp509ndash513 2004

[41] X Fu Y-Q Wang J Wang J Yu and G-C Wu ldquoChanges inexpression of nociceptinorphanin FQ and its receptor in spinaldorsal horn during electroacupuncture treatment for peripheralinflammatory pain in ratsrdquo Peptides vol 28 no 6 pp 1220ndash1228 2007

[42] L Qi H R Liu T Yi et al ldquoWarming moxibustion relieveschronic visceral hyperalgesia in rats Relations to spinal dynor-phin and orphanin-FQ systemrdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2013 Article ID 920675 10pages 2013

[43] M J Millan ldquoDescending control of painrdquo Progress in Neurobi-ology vol 66 no 6 pp 355ndash474 2002

[44] G-T Gim J-H Lee E Park et al ldquoElectroacupuncture atten-uates mechanical and warm allodynia through suppression ofspinal glial activation in a rat model of neuropathic painrdquo BrainResearch Bulletin vol 86 no 5-6 pp 403ndash411 2011

[45] S-Y Kang C-Y Kim D-H Roh et al ldquoChemical stimulationof the ST36 acupoint reduces both formalin-induced nocicep-tive behaviors and spinal astrocyte activation via spinal alpha-2adrenoceptorsrdquoBrain Research Bulletin vol 86 no 5-6 pp 412ndash421 2011

[46] Y Zhang R X Zhang M Zhang et al ldquoElectroacupunctureinhibition of hyperalgesia in an inflammatory pain rat modelInvolvement of distinct spinal serotonin and norepinephrinereceptor subtypesrdquo British Journal of Anaesthesia vol 109 no2 pp 245ndash252 2012

[47] W Kim S K Kim and B-I Min ldquoMechanisms ofelectroacupuncture-induced analgesia on neuropathic pain inanimal modelrdquo Evidence-Based Complementary and AlternativeMedicine vol 2013 Article ID 436913 11 pages 2013

[48] D S Park B K Seo and Y H Baek ldquoAnalgesic effect ofelectroacupuncture on inflammatory pain in collagen-inducedarthritis rats Mediation by alpha2- and beta-adrenoceptorsrdquoRheumatology International vol 33 no 2 pp 309ndash314 2013

[49] S Y Kang D H Roh H W Kim H J Han A J Beitz andJ H Lee ldquoSuppression of adrenal gland-derived epinephrineenhances the corticosterone-induced antinociceptive effect inthe mouse formalin testrdquo European Journal of Pain vol 18 no5 pp 617ndash628 2014

[50] H JMoon B-S LimD-I Lee et al ldquoEffects of electroacupunc-ture on oxaliplatin-induced neuropathic cold hypersensitivityin ratsrdquo e Journal of Physiological Sciences vol 64 no 2 pp151ndash156 2014

[51] J-W Choi S-Y Kang J-G Choi et al ldquoAnalgesic effectof electroacupuncture on paclitaxel-induced neuropathic painvia spinal opioidergic and adrenergic mechanisms in micerdquoAmerican Journal of Chinese Medicine vol 43 no 1 pp 57ndash702015

[52] J-H Yeo S-Y Yoon S-K Kwon et al ldquoRepetitive acupuncturepoint treatment with diluted bee venom relieves mechani-cal allodynia and restores intraepidermal nerve fiber loss inoxaliplatin-induced neuropathic micerdquoe Journal of Pain vol17 no 3 pp 298ndash309 2016

[53] J E Huh B K Seo J W Lee Y C Park and Y H Baek ldquoAnal-gesic effects of diluted bee venom acupuncture mediated bydelta-opioid and alpha2-adrenergic receptors in osteoarthriticratsrdquo Alternative erapies in Health and Medicine vol 24 no2 pp 28ndash35 2018

[54] W Chen B Song and J C Marvizon ldquoInhibition of opioidrelease in the rat spinal cord by alpha2C adrenergic receptorsrdquoNeuropharmacology vol 54 no 6 pp 944ndash953 2008

[55] B-K Seo W-S Sung Y-C Park and Y-H Baek ldquoTheelectroacupuncture-induced analgesic effect mediated by 5-HT1 5-HT3 receptor and muscarinic cholinergic receptors inrat model of collagenase-induced osteoarthritisrdquo BMC Comple-mentary and Alternative Medicine vol 16 no 1 article no 2122016

[56] S K Kim JH Park and S J Bae ldquoEffects of electroacupunctureon cold allodynia in a rat model of neuropathic pain Mediationby spinal adrenergic and serotonergic receptorsrdquo ExperimentalNeurology vol 195 no 2 pp 430ndash436 2005

[57] R Banzi C Cusi C Randazzo R Sterzi D Tedesco andL Moja ldquoSelective serotonin reuptake inhibitors (SSRIs) andserotonin-norepinephrine reuptake inhibitors (SNRIs) for theprevention of tension-type headache in adultsrdquo CochraneDatabase of Systematic Reviews vol 2015 no 5 article noCd011681 2015

[58] L Liu P Pei L-P Zhao Z-Y Qu Y-P Zhu and L-P WangldquoElectroacupuncture pretreatment at GB20 exerts antinocicep-tive effects via peripheral and central serotonin mechanism inconscious migraine ratsrdquo Evidence-Based Complementary andAlternative Medicine vol 2016 Article ID 1846296 10 pages2016

[59] R Zhang L Lao K Ren and B M Berman ldquoMechanisms ofacupuncture-electroacupuncture on persistent painrdquoAnesthesi-ology vol 120 no 2 pp 482ndash503 2014

[60] F-C Chang H-Y Tsai M-C Yu P-L Yi and J-G Lin ldquoThecentral serotonergic system mediates the analgesic effect ofelectroacupuncture on ZUSANLI (ST36) acupointsrdquo Journal ofBiomedical Science vol 11 no 2 pp 179ndash185 2004

[61] Z-Q Zhao ldquoNeural mechanism underlying acupuncture anal-gesiardquo Progress in Neurobiology vol 85 no 4 pp 355ndash375 2008

[62] C Y Chiang Z Li J O Dostrovsky J W Hu and B J SessleldquoGlutamine uptake contributes to central sensitization in themedullary dorsal hornrdquo NeuroReport vol 19 no 11 pp 1151ndash1154 2008


[63] CWenling Y Jun S Jing L Xiaochun andG Xinmin ldquoEffectsof electroacupuncture on the pain threshold and the NMDA R1mRNA in DRG on neuropathic pain ratsrdquo Journal of HuazhongUniversity of Science and Technology (Medical Sciences) vol 23no 2 pp 108ndash111 2003

[64] C Huang H-T Li Y-S Shi J-S Han and Y Wan ldquoKetaminepotentiates the effect of electroacupuncture on mechanicalallodynia in a rat model of neuropathic painrdquo NeuroscienceLetters vol 368 no 3 pp 327ndash331 2004

[65] B-T Choi J Kang and U-B Jo ldquoEffects of electroacupuncturewith different frequencies on spinal ionotropic glutamate recep-tor expression in complete Freundrsquos adjuvant-injected ratrdquoActaHistochemica vol 107 no 1 pp 67ndash76 2005

[66] S-L Tian X-Y Wang and G-H Ding ldquoRepeated electro-acupuncture attenuates chronic visceral hypersensitivity andspinal cord NMDA receptor phosphorylation in a rat irritablebowel syndromemodelrdquo Life Sciences vol 83 no 9-10 pp 356ndash363 2008

[67] Y-H Gao S-P Chen J-Y Wang L-N Qiao Q-L Xu andJ-L Liu ldquoEffects of electroacupuncture at different acupointson the pain behavior and NMDA receptor 2 B subunit mRNAandprotein expression andphosphorylation level in the cervicalspinal cord in rats with thyroid regional painrdquo Zhen Ci Yan Jiuvol 34 no 6 pp 376ndash382 2009

[68] X-M Feng S-P Chen J-Y Wang et al ldquoEffect of elec-troacupuncture intervention on expression of pain sensoryand affection processing related corticotropin-releasing factorreceptor mRNA etc in the amygdala in neuropathic pain andnegative affection ratsrdquo Zhen Ci Yan Jiu vol 39 no 6 pp 448ndash455 2014

[69] Y-Z Sun T-J Liu Z Wei H-Y Fan and H Luan ldquoEffectof electroacupuncture intervention on expression of NR 2 Bsubunit of NMDA receptor in amygdala during morphinewithdrawal in ratsrdquo Zhen Ci Yan Jiu vol 40 no 3 pp 210ndash2142015

[70] X Gao Y Qiao B Jia et al ldquoNMDA receptor-dependentsynaptic activity in dorsal motor nucleus of vagus mediatesthe enhancement of gastric motility by stimulating ST36rdquoEvidence-Based Complementary and Alternative Medicine vol2012 Article ID 438460 11 pages 2012

[71] J Dommerholt ldquoDry needlingmdashperipheral and central consid-erationsrdquo Journal ofManualampManipulativeerapy vol 19 no4 pp 223ndash237 2011

[72] DMNiddamR-C Chan S-H Lee T-C Yeh and J-CHsiehldquoCentral representation of hyperalgesia frommyofascial triggerpointrdquo NeuroImage vol 39 no 3 pp 1299ndash1306 2008

[73] R-DGosselinMR Suter R-R Ji and IDecosterd ldquoGlial cellsand chronic painrdquoe Neuroscientist vol 16 no 5 pp 519ndash5312010

[74] M Chacur D Lambertz U Hoheisel and S Mense ldquoRole ofspinal microglia in myositis-induced central sensitisation Animmunohistochemical and behavioural study in ratsrdquo EuropeanJournal of Pain vol 13 no 9 pp 915ndash923 2009

[75] Y Wang R Gehringer S A Mousa D Hackel A Brack andH L Rittner ldquoCXCL10 controls inflammatory pain via opioidpeptide-containing macrophages in electroacupuncturerdquo PLoSONE vol 9 no 4 Article ID e94696 2014

[76] D Phillip A C Lyngberg and R Jensen ldquoAssessment ofheadache diagnosis A comparative population study of a clin-ical interview with a diagnostic headache diaryrdquo Cephalalgiavol 27 no 1 pp 1ndash8 2007

[77] Y Chen ldquoAdvances in the pathophysiology of tension-typeheadache From stress to central sensitizationrdquoCurrent Pain andHeadache Reports vol 13 no 6 pp 484ndash494 2009

[78] R R Ji T Kohno K A Moore and C J Woolf ldquoCentralsensitization and LTP Do pain and memory share similarmechanismsrdquo Trends in Neurosciences vol 26 no 12 pp 696ndash705 2003

[79] C DMunhoz B Garcıa-Bueno J L MMadrigal L B LepschC Scavone and J C Leza ldquoStress-induced neuroinflammationMechanisms and new pharmacological targetsrdquo Brazilian Jour-nal of Medical and Biological Research vol 41 no 12 pp 1037ndash1046 2008

[80] C-H Zhao M J Stillman and T D Rozen ldquoTraditional andevidence-based acupuncture in headachemanagementTheorymechanism and practicerdquo Headache e Journal of Head andFace Pain vol 45 no 6 pp 716ndash730 2005

[81] V Neugebauer W Li G C Bird G Bhave and R W GereauldquoSynaptic plasticity in the amygdala in amodel of arthritic painDifferential roles of metabotropic glutamate receptors 1 and 5rdquoe Journal of Neuroscience vol 23 no 1 pp 52ndash63 2003

[82] N Boyer R Dallel A Artola and L Monconduit ldquoGeneraltrigeminospinal central sensitization and impaired descendingpain inhibitory controls contribute to migraine progressionrdquoPain vol 155 no 7 pp 1196ndash1205 2014

[83] M Langemark F W Bach T S Jensen and J OlesenldquoDecreased nociceptive flexion reflex threshold in chronictension-type headacherdquo JAMA Neurology vol 50 no 10 pp1061ndash1064 1993

[84] L Bendtsen ldquoCentral sensitization in tension-type headache -Possible pathophysiological mechanismsrdquo Cephalalgia vol 20no 5 pp 486ndash508 2000

[85] C Fernandez-de-las-PenasM L Cuadrado L Arendt-NielsenD G Simons and J A Pareja ldquoMyofascial trigger pointsand sensitization An updated pain model for tension-typeheadacherdquo Cephalalgia vol 27 no 5 pp 383ndash393 2007

[86] M Chassot J A Dussan-Sarria F C Sehn et al ldquoElec-troacupuncture analgesia is associated with increased serumbrain-derived neurotrophic factor in chronic tension-typeheadache A randomized sham controlled crossover trialrdquoBMC Complementary and Alternative Medicine vol 15 articleno 144 2015

[87] R M Edelmayer T W Vanderah L Majuta et al ldquoMedullarypain facilitating neurons mediate allodynia in headache-relatedpainrdquo Annals of Neurology vol 65 no 2 pp 184ndash193 2009

[88] R BursteinM F Cutrer andD Yarnitsky ldquoThe development ofcutaneous allodynia during a migraine attack clinical evidencefor the sequential recruitment of spinal and supraspinal noci-ceptive neurons in migrainerdquo Brain vol 123 no 8 pp 1703ndash1709 2000

[89] C-S Jia X-S Ma J Shi et al ldquoElectroacupuncture at Qiuxu(GB 40) for treatment of migraine- -a clinical multicentral ran-dom controlled studyrdquo Journal of Traditional Chinese Medicinevol 29 no 1 pp 43ndash49 2009

[90] H Zhang S-D He Y-P Hu and H Zheng ldquoAntagonismof cannabinoid receptor 1 attenuates the anti-inflammatoryeffects of electroacupuncture in a rodent model of migrainerdquoAcupuncture in Medicine vol 34 no 6 pp 463ndash470 2016

[91] R M Jensen A Lyngberg and R H Jensen ldquoBurden of clusterheadacherdquo Cephalalgia vol 27 no 6 pp 535ndash541 2007

[92] A Ashkenazi ldquoAllodynia in cluster headacherdquoCurrent Pain andHeadache Reports vol 14 no 2 pp 140ndash144 2010


[93] C Fernandez-de-las-Penas R Ortega-Santiago M LCuadrado C Lopez-de-Silanes and J A Pareja ldquoBilateralwidespread mechanical pain hypersensitivity as sign of centralsensitization in patients with cluster headacherdquo Headache eJournal of Head and Face Pain vol 51 no 3 pp 384ndash391 2011

[94] A D Mosnaim P Maturana J Puente and M E WolfldquoDecreased plasma methionine-enkephalin levels in clusterheadache patientsrdquoAmerican Journal oferapeutics vol 19 no3 pp 174ndash179 2012

[95] J E Hardebo R Ekman and M Eriksson ldquoLow CSF met-enkephalin levels in cluster headache are elevated by acupunc-turerdquo Headache e Journal of Head and Face Pain vol 29 no8 pp 494ndash497 1989

[96] O Van Hecke S K Austin R A Khan B H Smith andN Torrance ldquoNeuropathic pain in the general population Asystematic review of epidemiological studiesrdquo Pain vol 155 no4 pp 654ndash662 2014

[97] T S Jensen and N B Finnerup ldquoAllodynia and hyperalgesiain neuropathic pain Clinical manifestations and mechanismsrdquoe Lancet Neurology vol 13 no 9 pp 924ndash935 2014

[98] A H Landerholm and P T Hansson ldquoMechanisms of dynamicmechanical allodynia and dysesthesia in patients with periph-eral and central neuropathic painrdquo European Journal of Painvol 15 no 5 pp 498ndash503 2011

[99] J-Y Park J J Park S Jeon et al ldquoFrom peripheral to centralThe role of ERK signaling pathway in acupuncture analgesiardquoe Journal of Pain vol 15 no 5 pp 535ndash549 2014

[100] J V Berger L Knaepen S P M Janssen et al ldquoCellularand molecular insights into neuropathy-induced pain hyper-sensitivity for mechanism-based treatment approachesrdquo BrainResearch Reviews vol 67 no 1-2 pp 282ndash310 2011

[101] J A M Coull S Beggs D Boudreau et al ldquoBDNF frommicroglia causes the shift in neuronal anion gradient underlyingneuropathic painrdquo Nature vol 438 no 7070 pp 1017ndash10212005

[102] S P Janssen M Truin M Van Kleef and E A JoostenldquoDifferential GABAergic disinhibition during the developmentof painful peripheral neuropathyrdquo Neuroscience vol 184 pp183ndash194 2011

[103] C A von Hehn R Baron and C J Woolf ldquoDeconstructingthe neuropathic pain phenotype to reveal neural mechanismsrdquoNeuron vol 73 no 4 pp 638ndash652 2012

[104] Y-H Gao J-Y Wang L-N Qiao et al ldquoNK cells mediate thecumulative analgesic effect of electroacupuncture in a ratmodelof neuropathic painrdquo BMC Complementary and AlternativeMedicine vol 14 no 1 article no 316 2014

[105] C H Lau X Wu V C Chung et al ldquoAcupuncture and relatedtherapies for symptom management in palliative cancer careSystematic review andmeta-analysisrdquoMedicine (Baltimore) vol95 no 9 p e2901 2016

[106] D J Kopsky and J M K Hesselink ldquoMultimodal stepped careapproach with acupuncture and PPAR-alpha agonist palmi-toylethanolamide in the treatment of a patient with multi-ple sclerosis and central neuropathic painrdquo Acupuncture inMedicine vol 30 no 1 pp 53ndash55 2012

[107] L Chen C C Lin TW Huang et al ldquoEffect of acupuncture onaromatase inhibitor-induced arthralgia in patients with breastcancer Ameta-analysis of randomized controlled trialsrdquoBreastvol 33 pp 132ndash138 2017

[108] G T Lewith J Field and D Machin ldquoAcupuncture comparedwith placebo in post-herpetic painrdquo Pain vol 17 no 4 pp 361ndash368 1983

[109] R W Johnson G Wasner P Saddier and R Baron ldquoHerpeszoster and postherpetic neuralgia Optimizing management inthe elderly patientrdquoDrugs amp Aging vol 25 no 12 pp 991ndash10062008

[110] B F Jung R W Johnson D R J Griffin and R H DworkinldquoRisk factors for postherpetic neuralgia in patients with herpeszosterrdquo Neurology vol 62 no 9 pp 1545ndash1551 2004

[111] CWu Z Lv Y Zhao et al ldquoElectroacupuncture improves ther-mal and mechanical sensitivities in a rat model of postherpeticneuralgiardquoMolecular Pain vol 9 article no 18 2013

[112] H-C Hsu N-Y Tang Y-W Lin T-C Li H-J Liu and C-L Hsieh ldquoEffect of electroacupuncture on rats with chronicconstriction injury-induced neuropathic painrdquo e ScientificWorld Journal vol 2014 Article ID 129875 9 pages 2014

[113] Z-S Liu W-N Peng B-Y Liu et al ldquoClinical practiceguideline of acupuncture for herpes zosterrdquo Chinese Journal ofIntegrative Medicine vol 19 no 1 pp 58ndash67 2013

[114] D Leclercq J-B Thiebaut and F Heran ldquoTrigeminal neural-giardquo Diagnostic and Interventional Imaging vol 94 no 10 pp993ndash1001 2013

[115] G Nappi F Facchinetti G Bono et al ldquoPlasma opioid levelsin post-traumatic chronic headache and trigeminal neuralgiaMaintained response to acupuncturerdquoHeadachee Journal ofHead and Face Pain vol 22 no 6 pp 276ndash279 1982

[116] M Davies S Brophy R Williams and A Taylor ldquoTheprevalence severity and impact of painful diabetic peripheralneuropathy in type 2 diabetesrdquo Diabetes Care vol 29 no 7 pp1518ndash1522 2006

[117] B S Galer A Gianas and M P Jensen ldquoPainful diabeticpolyneuropathy Epidemiology pain description and quality ofliferdquo Diabetes Research and Clinical Practice vol 47 no 2 pp123ndash128 2000

[118] X-L Wang H-M Zhang S-R Chen and H-L Pan ldquoAlteredsynaptic input and GABAB receptor function in spinal superfi-cial dorsal horn neurons in rats with diabetic neuropathyrdquoeJournal of Physiology vol 579 no 3 pp 849ndash861 2007

[119] J-Q Li S-R Chen H Chen Y-Q Cai and H-L PanldquoRegulation of increased glutamatergic input to spinal dorsalhorn neurons bymGluR5 in diabetic neuropathic painrdquo Journalof Neurochemistry vol 112 no 1 pp 162ndash172 2010

[120] A K Schreiber C F Nones R C Reis J G Chichorro andJ M Cunha ldquoDiabetic neuropathic pain Physiopathology andtreatmentrdquoWorld Journal of Diabetes vol 6 no 3 pp 432ndash4442015

[121] H-P Bai P Liu Y-M Wu W-Y Guo Y-X Guo and X-LWang ldquoActivation of spinal GABAB receptors normalizes N-methyl-D-aspartate receptor in diabetic neuropathyrdquo Journal ofthe Neurological Sciences vol 341 no 1-2 pp 68ndash72 2014

[122] C Morgado L Silva P Pereira-Terra and I Tavares ldquoChangesin serotoninergic and noradrenergic descending pain pathwaysduring painful diabetic neuropathy The preventive action ofIGF1rdquo Neurobiology of Disease vol 43 no 1 pp 275ndash284 2011

[123] A Bailey D Wingard M Allison P Summers and D CalacldquoAcupuncture treatment of diabetic peripheral neuropathy in anamerican indian communityrdquo JAMS Journal of Acupuncture andMeridian Studies vol 10 no 2 pp 90ndash95 2017

[124] B B Abuaisha J B Costanzi and A J M Boulton ldquoAcupunc-ture for the treatment of chronic painful peripheral diabeticneuropathy A long-term studyrdquo Diabetes Research and ClinicalPractice vol 39 no 2 pp 115ndash121 1998


[125] E Jeon H O Kwon I Shin S Kang and H ShonldquoEffect of acupuncture on diabetic peripheral neuropathy Anuncontrolled preliminary study from Koreardquo Acupuncture inMedicine vol 32 no 4 pp 350ndash352 2014

[126] C Zhang Y-X Ma and Y Yan ldquoClinical effects of acupunc-ture for diabetic peripheral neuropathyrdquo Journal of TraditionalChinese Medicine vol 30 no 1 pp 13-14 2010

[127] L Shi H-H Zhang Y Xiao J Hu and G-Y Xu ldquoElec-troacupuncture suppresses mechanical allodynia and nuclearfactor kappa B signaling in streptozotocin-induced diabeticratsrdquo CNS Neuroscience amperapeutics vol 19 no 2 pp 83ndash902013

[128] L Manni F Florenzano and L Aloe ldquoElectroacupuncturecounteracts the development of thermal hyperalgesia and thealteration of nerve growth factor and sensory neuromodulatorsinduced by streptozotocin in adult ratsrdquo Diabetologia vol 54no 7 pp 1900ndash1908 2011

[129] B Kumar J Kalita G Kumar and U K Misra ldquoCentralpoststroke pain A review of pathophysiology and treatmentrdquoAnesthesia amp Analgesia vol 108 no 5 pp 1645ndash1657 2009

[130] U K Misra J Kalita and B Kumar ldquoA study of clinical mag-netic resonance imaging and somatosensory-evoked potentialin central post-stroke painrdquo e Journal of Pain vol 9 no 12pp 1116ndash1122 2008

[131] D Bowsher ldquoPain after thalamic stroke Right diencephalicpredominance and clinical features in 180 patientsrdquo Neurologyvol 51 no 3 pp 927-928 1998

[132] G E Gamble E Barberan H-U Laasch D Bowsher PJ Tyrrell and A K P Jones ldquoPoststroke shoulder pain Aprospective study of the association and risk factors in 152patients from a consecutive cohort of 205 patients presentingwith strokerdquo European Journal of Pain vol 6 no 6 pp 467ndash4742002

[133] M Roosink R T Van Dongen J R Buitenweg G J Ren-zenbrink A C Geurts and M J Ijzerman ldquoMultimodal andwidespread somatosensory abnormalities in persistent shoulderpain in the first 6 months after stroke An exploratory studyrdquoArchives of Physical Medicine and Rehabilitation vol 93 no 11pp 1968ndash1974 2012

[134] C-H Lin K-H Chen C-H Chang et al ldquoMuscle pain inten-sity and pressure pain threshold changes in different periodsof stroke patientsrdquo American Journal of Physical Medicine ampRehabilitation vol 93 no 4 pp 299ndash309 2014

[135] G M Schneider A D Smith A Hooper et al ldquoMinimizingthe source of nociception and its concurrent effect on sensoryhypersensitivity An exploratory study in chronic whiplashpatientsrdquo BMC Musculoskeletal Disorders vol 11 article no 292010

[136] J Lorenz H Kohlhoff H-C Hansen K Kunze and B BrommldquoAbeta-fiber mediated activation of cingulate cortex as correlateof central post-stroke painrdquo NeuroReport vol 9 no 4 pp 659ndash663 1998

[137] D Bowsher ldquoAllodynia in relation to lesion site in central post-stroke painrdquoe Journal of Pain vol 6 no 11 pp 736ndash740 2005

[138] M Roosink G J Renzenbrink J R Buitenweg R T M VanDongen A C H Geurts and M J Ijzerman ldquoSomatosensorysymptoms and signs and conditioned pain modulation inchronic post-stroke shoulder painrdquoe Journal of Pain vol 12no 4 pp 476ndash485 2011

[139] G Zeilig M Rivel D Doron and R Defrin ldquoDoes hemiplegicshoulder pain share clinical and sensory characteristics with

central neuropathic pain Acomparative studyrdquo European Jour-nal of Physical and Rehabilitation Medicine vol 52 no 5 pp662ndash671 2016

[140] S Pertoldi and P Di Benedetto ldquoShoulder-hand syndrome afterstroke A complex regional pain syndromerdquo Europa Medico-physica vol 41 no 4 pp 283ndash292 2005

[141] A Yermakova and M K OrsquoBanion ldquoCyclooxygenases in thecentral nervous system Implications for treatment of neurolog-ical disordersrdquo Current Pharmaceutical Design vol 6 no 17 pp1755ndash1776 2000

[142] S Cho G Jahng S Park W Jung S Moon and J ParkldquofMRI study of effect on brain activity according to stimula-tion method at LI11 ST36 Painful pressure and acupuncturestimulation of same acupointsrdquo Journal of Alternative andComplementary Medicine vol 16 no 4 pp 489ndash495 2010

[143] J Salom-Moreno Z Sanchez-Mila R Ortega-Santiago MPalacios-Cena S Truyol-Domınguez and C Fernandez-De-Las-Penas ldquoChanges in spasticity widespread pressure painsensitivity and baropodometry after the application of dryneedling in patients who have had a stroke A randomizedcontrolled trialrdquo Journal of Manipulative and Physiologicalerapeutics vol 37 no 8 pp 569ndash579 2014

[144] H Bahrami-Taghanaki Y Liu H Azizi et al ldquoA randomizedcontrolled trial of acupuncture for chronic low-back painrdquoAlternative erapies in Health and Medicine vol 20 no 3 pp13ndash19 2014

[145] M Imamura J Chen S R Matsubayashi et al ldquoChanges inpressure pain threshold in patients with chronic nonspecific lowback painrdquoe Spine Journal (Phila Pa 1976) vol 38 no 24 pp2098ndash2107 2013

[146] N A Roussel J Nijs M Meeus V Mylius C Fayt and ROostendorp ldquoCentral sensitization and altered central painprocessing in chronic low back pain Fact ormythrdquoeClinicalJournal of Pain vol 29 no 7 pp 625ndash638 2013

[147] M Lam R Galvin and P Curry ldquoEffectiveness of acupuncturefor nonspecific chronic low back pain A systematic review andmeta-analysisrdquoe Spine Journal (Phila Pa 1976) vol 38 no 24pp 2124ndash2138 2013

[148] R Chen J Xiong Z Chi and B Zhang ldquoHeat-sensitivemoxibustion for lumbar disc herniation A meta-analysis ofrandomized controlled trialsrdquo Journal of Traditional ChineseMedicine vol 32 no 3 pp 322ndash328 2012

[149] F Liao C Zhang Z Bian et al ldquoCharacterizing heat-sensitization responses in suspended moxibustion with high-density EEGrdquo Pain Medicine vol 15 no 8 pp 1272ndash1281 2014

[150] Y Liao X Li N Li and J Zhou ldquoElectroacupuncture pro-tects against articular cartilage erosion by inhibiting mitogen-activated protein kinases in a rat model of osteoarthritisrdquoAcupuncture in Medicine vol 34 no 4 pp 290ndash295 2016

[151] B M Berman L Lao P Langenberg W L Lee A MGilpin and M C Hochberg ldquoEffectiveness of acupuncture asadjunctive therapy in osteoarthritis of the knee A randomizedcontrolled trialrdquo Annals of Internal Medicine vol 141 no 12 pp901ndash910 2004

[152] E Lluch R Torres J Nijs and J Van Oosterwijck ldquoEvidencefor central sensitization in patients with osteoarthritis pain Asystematic literature reviewrdquo European Journal of Pain vol 18no 10 pp 1367ndash1375 2014

[153] B K Seo D S Park and Y H Baek ldquoThe analgesic effect ofelectroacupuncture on inflammatory pain in the rat model of


collagenase-induced arthritis Mediation by opioidergic recep-torsrdquo Rheumatology International vol 33 no 5 pp 1177ndash11832013

[154] S V Eriksson T Lundeberg and S Lundeberg ldquoInteraction ofdiazepam and naloxone on acupuncture induced pain reliefrdquoAmerican Journal of ChineseMedicine vol 19 no 1 pp 1ndash7 1991

[155] N Uryu K Okada and K Kawakita ldquoAnalgesic effects of indi-rectmoxibustion on an experimental ratmodel of osteoarthritisin the kneerdquoAcupuncture inMedicine vol 25 no 4 pp 175ndash1832007

[156] A M Accarino F Azpiroz and J-R Malagelada ldquoSelectivedysfunction of mechanosensitive intestinal afferents in irritablebowel syndromerdquoGastroenterology vol 108 no 3 pp 636ndash6431995

[157] G N Verne M E Robinson and D D Price ldquoHypersensitivityto visceral and cutaneous pain in the irritable bowel syndromerdquoPain vol 93 no 1 pp 7ndash14 2001

[158] G-Q Chao and S Zhang ldquoEffectiveness of acupuncture to treatirritable bowel syndrome A meta-analysisrdquo World Journal ofGastroenterology vol 20 no 7 pp 1871ndash1877 2014

[159] H MacPherson H Tilbrook J M Bland et al ldquoAcupuncturefor irritable bowel syndrome Primary care based pragmaticrandomised controlled trialrdquo BMC Gastroenterology vol 12article no 150 2012

[160] E Manheimer K Cheng L S Wieland et al ldquoAcupuncture fortreatment of irritable bowel syndromerdquo Cochrane Database ofSystematic Reviews vol 5 Article ID CD005111 2012

[161] J H Sun X LWu C Xia et al ldquoClinical evaluation of SoothingGan and invigorating Pi acupuncture treatment on diarrhea-predominant irritable bowel syndromerdquo Chinese Journal ofIntegrative Medicine vol 17 no 10 pp 780ndash785 2011

[162] X Y Tian Z X Bian X G Hu X J Zhang L Liuand H Zhang ldquoElectro-acupuncture attenuates stress-induceddefecation in rats with chronic visceral hypersensitivity viaserotonergic pathwayrdquo Brain Research vol 1088 no 1 pp 101ndash108 2006

[163] H-R Liu X-MWang E-H Zhou et al ldquoAcupuncture at bothST25 and ST37 improves the pain threshold of chronic visceralhypersensitivity ratsrdquoNeurochemical Research vol 34 no 11 pp1914ndash1918 2009

[164] X P Ma L-Y Tan Y Yang et al ldquoEffect of electro-acupunctureon substance P its receptor and corticotropin-releasing hor-mone in rats with irritable bowel syndromerdquo World Journal ofGastroenterology vol 15 no 41 pp 5211ndash5217 2009

[165] H-G Wu B Jiang E-H Zhou et al ldquoRegulatory mechanismof electroacupuncture in irritable bowel syndrome PreventingMC activation and decreasing SP VIP secretionrdquo DigestiveDiseases and Sciences vol 53 no 6 pp 1644ndash1651 2008

[166] J-H Sun X-L Wu Y-F Meng et al ldquoElectro-acupuncturedecreases 5-HT CGRP and increases NPY in the brain-gutaxis in two rat models of Diarrhea-predominant irritablebowel syndrome(D-IBS)rdquoBMCComplementary andAlternativeMedicine vol 15 article no 340 2015

[167] H-G Wu H-R Liu Z-A Zhang et al ldquoElectro-acupuncturerelieves visceral sensitivity and decreases hypothalamiccorticotropin-releasing hormone levels in a rat model ofirritable bowel syndromerdquo Neuroscience Letters vol 465 no 3pp 235ndash237 2009

[168] J CWu E T Ziea L Lao et al ldquoEffect of electroacupuncture onvisceral hyperalgesia serotonin and fos expression in an animalmodel of irritable bowel syndromerdquo Journal of Neurogastroen-terology and Motility vol 16 no 3 pp 306ndash314 2010

[169] W-L Zhu Y Li H-F Wei et al ldquoEffect of electro-acupunctureat different acupoints on neuropeptide and somatostatin inrat brain with irritable bowel syndromerdquo Chinese Journal ofIntegrative Medicine vol 18 no 4 pp 288ndash292 2012

[170] D-B Qi and W-M Li ldquoEffects of electroacupuncture onexpression of c-fos protein and N-methyl-D-aspartate receptor1 in the rostral ventromediamedulla of ratswith chronic visceralhyperalgesiardquo Zhong Xi Yi Jie He Xue Bao (Journal of ChineseIntegrative Medicine) vol 10 no 4 pp 416ndash423 2012

Stem Cells International

Hindawiwwwhindawicom Volume 2018


MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



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PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine


Behavioural Neurology

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Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom


PubMed database 1766 articles

Cochrane database 6 articles

1772 articles

313 articles

170 articles

49 articles49 articles72 articles

Exclude 1459 articles1 No abstract2 Not related to acupuncture and

central sensitization in abstract

Exclude 143 articles1 Not available for full text2 Not related to acupuncture and

central sensitization in full text

ReviewClinical trialsBasic research

Figure 1 Flow chart of the search processes

and increase in glutamate receptor function in the second-order neurons as well as disinhibition of local inhibitory120574-aminobutyric acid (GABA)ergic and glycinergic interneu-rons in the dorsal horn of the spinal cord and (3) releaseof cytokines and chemokines caused by the activation ofspinal microglia and astrocytes [7] Hyperalgesia (increasedpain sensitivity) and allodynia (pain production induced by anonnociceptive stimulation) are the two main characteristicsof central sensitization [5] Many clinical syndromesmdashsuchas rheumatoid arthritis osteoarthritis temporomandibulardisorders fibromyalgia musculoskeletal disorders tension-type headache neuropathic pain complex regional painsyndrome and postsurgical painmdashmay contribute to centralsensitization [4]

Acupuncture is a well-known treatment modality thatoriginated in China This procedure includes the insertion ofneedles into specific points of the body (called acupoints) toachieve therapeutic effects According to the theory of tra-ditional Chinese medicine (TCM) acupuncture modulatesthe flow of Qi and blood through the meridians and restoresthe balance of the five organs to maintain homeostasis [8]To date acupuncture is considered a valid treatment methodfor alleviating acute and chronic pain in clinical practiceMany studies have discussed the possible mechanism of painreduction through acupuncture treatment

In this article we review the mechanisms of pain thecauses of central sensitization and the mechanisms under-lying acupuncture analgesia

2 Methods

We searched the PubMed database and Cochrane databasefor studies published unlimited beginning date to November2017 The keywords included ldquoacupuncturerdquo ldquopathophysiol-ogyrdquo ldquocentral sensitizationrdquo ldquoanalgesiardquo and ldquopainrdquo Lan-guage was limited to English and Chinese The filter processwas firstly by search engine of the website which yielded 1772articles We excluded 1459 articles due to no abstract or not

related to acupuncture and central sensitization in abstractby the authors which yielded 313 articles We excluded 143articles due to no full text or not related to acupunctureand central sensitization in full text by the authors whichyielded 170 articles Therefore the basic clinical and reviewarticle were 72 49 and 49 respectively in type of articleThe manuscript included basic and clinical studies related tocentral sensitization and acupuncture analgesia Flow chart ofthe search processes was as shown in Figure 1

21 Physiology of Pain Somatic sensations are relays fromthe peripheral receptors to the brain cortex Signals aretransferred from distal nociceptors to the dorsal horn ofthe spinal cord (synapsing on second-order neurons) andthrough the brainstem to the ventral posterolateral nucleus ofthe thalamus Finally the signals are projected to the postcen-tral gyrus of the parietal cortex The ascending transductionis called the lateral spinothalamic pathway or anterolateralsystem [9ndash11]

The descending modulatory pathway plays a crucial rolein acupuncture analgesia The pathway includes the cortexventrolateral (vl) periaqueductal gray (PAG vlPAG) matterrostral ventromedial medulla (RVM) locus coeruleus raphenucleus and inhibitory synapses in the dorsal horn of thespinal cord [12]

22 Mechanism of Pain-Induced Central Sensitization Thesensory processing of pain is similar to a neural relay fromthe distinct pain-affected region of the body to the braincortex The upregulation or downregulation of each gatewould interfere with the ldquofeelingrdquo of ordinary sensationsThe threshold for activating primary afferent nociceptorsis reduced under intense repeated or prolonged stimuliThe relatively low threshold of the nerve ending contributesto a relatively high frequency of firing for stimuli of allintensities Central sensitization occurs with inflammatorymediators such as bradykinin nerve-growth factor someprostaglandins leukotrienes and nitric oxide [13] After


GlutamateAdenosine

BDNF


Prolonged stimuli



Limbic system





























































3 Conclusion








Acknowledgments


References






















































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















GlutamateAdenosine

BDNF


Prolonged stimuli



Limbic system





























































3 Conclusion








Acknowledgments


References






















































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of































































3 Conclusion








Acknowledgments


References






















































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






















































3 Conclusion








Acknowledgments


References






















































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of








































3 Conclusion








Acknowledgments


References






















































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of





























3 Conclusion








Acknowledgments


References






















































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Acknowledgments


References






















































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of








































































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of









































































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of










































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of









































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of










































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















Documents

Acupuncture-Analgesia-Mediated Alleviation of Central ...downloads.hindawi.com/journals/ecam/2019/6173412.pdf · synaptic facilitation and engage central sensitization-like mechanisms