Acupuncture modulates resting state connectivity in default and sensorimotor brain networks

Previous studies have defined low-frequency, spatially consistent networks in resting fMRI data which may reflect functional connectivity. We sought to explore how a complex somatosensory stimulation, acupuncture, influences intrinsic connectivity in two of these networks: the default mode network (DMN) and sensorimotor network (SMN). We analyzed resting fMRI data taken before and after verum and sham acupuncture. Electrocardiography data were used to infer autonomic modulation through measures of heart rate variability (HRV). Probabilistic independent component analysis was used to separate resting fMRI data into DMN and SMN components. Following verum, but not sham, acupuncture there was increased DMN connectivity with pain (anterior cingulate cortex (ACC), periaqueductal gray), affective (amygdala, ACC), and memory (hippocampal formation, middle temporal gyrus) related brain regions. Furthermore, increased DMN connectivity with the hippocampal formation, a region known to support memory and interconnected with autonomic brain regions, was negatively correlated with acupuncture-induced increase in a sympathetic related HRV metric (LFu), and positively correlated with a parasympathetic related metric (HFu). Following verum, but not sham, acupuncture there was also increased SMN connectivity with pain-related brain regions (ACC, cerebellum). We attribute differences between verum and sham acupuncture to more varied and stronger sensations evoked by verum acupuncture. Our results demonstrate for the first time that acupuncture can enhance the post-stimulation spatial extent of resting brain networks to include anti-nociceptive, memory, and affective brain regions. This modulation and sympathovagal response may relate to acupuncture analgesia and other potential therapeutic effects.     

A psychophysical analysis of acupuncture analgesia

A psychophysical analysis of acupuncture analgesia was carried out in which low back pain patients made visual analogue scale (VAS) responses both to their chronic pain and to different levels of experimental heat pain (5 sec exposures to 43–51 °C) before and after electroacupuncture. VAS (sensory) responses to chronic pain, direct temperature matches to chronic pain, and VAS (sensory) responses to experimental pain were reduced in an internally consistent manner 1–2 h after treatment. The magnitude of this analgesic response was similar for dermatomes within the region of chronic pain and acupuncture needle placement (lower back) as well as for dermatomes remote from needle placement and chronic pain (forearm). Individual patients manifested either (1) a central-inhibitory pattern of analgesia wherein experimental and chronic pain in back regions and experimental pain in forearm regions were reduced, or (2) an origin-specific pattern wherein only the chronic low back pain was reduced. Patients tested several days after treatment all manifested the latter pattern of analgesia. VAS sensory and VAS affective analgesic responses to electroacupuncture treatment showed a delayed onset (1–24 h) to maximum effect and a duration of 10–14 days. Cumulative sensory and affective analgesic effects were observed at the end of 4 months of biweekly acupuncture treatments. The results of this analysis reveal the unique spatial and temporal properties of electroacupuncture analgesia and the extent to which it is mediated by at least two different mechanisms.     

The Role of Skin Mast Cells in Acupuncture Induced Analgesia in Animals: A Preclinical Systematic Review and Meta-analysis

While mast cells (MCs) are previously well-known as a pathological indicator of pain, their role in alleviating pain is recently emerged in acupuncture research. Thus, this study systematically reviews the role of MC in acupuncture analgesia. Animal studies on MC changes associated with the acupuncture analgesia were searched in PubMed and EMBASE. The MC number, degranulation ratio and pain threshold changes were collected as outcome measures for meta-analyses. Twenty studies were included with 13 suitable for meta-analysis, most with a moderate risk of bias. A significant MC degranulation after acupuncture was indicated in the normal and was significantly higher in the pain model. In the subgroup analysis by acupuncture type, manual (MA) and electrical (EA, each P < .00001) but not sham acupuncture had significant MC degranulation. Meta-regression revealed the linear proportionality between MC degranulation and acupuncture-induced analgesia (P < .001), which was found essential in MA (P < .00001), but not in EA (P = .45). MC mediators, such as adenosine and histamine, are involved in its mechanism. Taken together, skin MC is an essential factor for acupuncture-induced analgesia, which reveals a new aspect of MC as a pain alleviator. However, its molecular mechanism requires further study.PerspectiveThis systematic review synthesizes data from studies that examined the contribution of skin MC in acupuncture analgesia. Current reports suggest a new role for skin MC and its mediators in pain alleviation and explain a peripheral mechanism of acupuncture analgesia, with suggesting the need of further studies to confirm these findings.     

Modulation of shock-elicited pain by acupuncture and suggestion.

An experimental investigation of acupuncture's analgesic potency, separated from suggestion effects, is described, in which judgments of shock-elicited pain of the forearm were recorded along two separate scales: intensity and aversiveness. Data from experimental subjects, who received electrical acupunctural stimulation through surface electrodes located over acupuncture points and were given explicit counter-suggestions of sensitization, were compared to those obtained from control subjects, who received such stimulation over incorrect loci and were given explicit suggestions of analgesia. No alterations in the perception of pain intensity, either by acupunctural stimulation or suggestion, could be detected at any time during the experiment, but stimulation of the correct points produced a significant analgesic reduction in aversiveness which was specific to the arm so stimulated, overcame the counter-suggestion of sensitization, and persisted after stimulation was discontinued. No significant reductions were recorded from control subjects. These findings are interpreted in light of other experimental acupuncture research, and of the demonstrated mode of action of analgesics of proven efficacy.     

A Functional Neuroimaging Study of Expectancy Effects on Pain Response in Patients With Knee Osteoarthritis

Placebo treatments and healing rituals share much in common, such as the effects of expectancy, and have been used since the beginning of human history to treat pain. Previous mechanistic neuroimaging studies investigating the effects of expectancy on placebo analgesia have used young, healthy volunteers. Using functional magnetic resonance imaging (fMRI), we aimed to investigate the neural mechanisms by which expectancy evokes analgesia in older adults living with a chronic pain disorder and determine whether there are interactions with active treatment. In this fMRI study, we investigated the brain networks underlying expectancy in participants with chronic pain due to knee osteoarthritis (OA) after verum (genuine) and sham electroacupuncture treatment before and after experiencing calibrated experimental heat pain using a well tested expectancy manipulation model. We found that expectancy significantly and similarly modulates the pain experience in knee OA patients in both verum (n?=?21, 11 female; mean?±?SD age 57?±?7 years) and sham (n?=?22, 15 female; mean?±?SD age 59?±?7 years) acupuncture treatment groups. However, there were different patterns of changes in fMRI indices of brain activity associated with verum and sham treatment modalities specifically in the lateral prefrontal cortex. We also found that continuous electroacupuncture in knee OA patients can evoke significant regional coherence decreases in pain associated brain regions. Our results suggest that expectancy modulates the experience of pain in knee OA patients but may work through different pathways depending on the treatment modality and, we speculate, on pathophysiological states of the participants.

Involvement of Spinal Neurotrophin-3 in Electroacupuncture Analgesia and Inhibition of Spinal Glial Activation in Rat Model of Monoarthritis

Although electroacupuncture (EA) has been proven to effectively relieve pain associated with arthritis, the underlying mechanism of EA analgesia requires further investigation. Here, the involvement of spinal neurotrophin-3 (NT-3) in EA’s analgesic effects on complete Freund’s adjuvant (CFA)-induced inflammatory pain was examined. The present study demonstrated that: 1) repeated EA stimulation of ipsilateral GB30 and GB34 acupoints remarkably suppressed CFA-induced hyperalgesia; 2) EA treatment markedly enhanced the upregulation of spinal NT-3 mRNA and protein levels following CFA injection; 3) antisense oligodeoxynucleotides (ODN) specifically against NT-3 intrathecally administered during EA treatment for 7 days significantly attenuated the EA analgesia; and 4) the suppressed expression of spinal GFAP (astrocytic marker), OX-42 (microglial marker) as well as proinflammatory cytokines, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α by EA treatment was significantly attenuated following NT-3 antisense ODN delivery. These results suggested that endogenous NT-3 may be involved in the analgesic effect of EA on inflammatory pain in rats, mediated through the inhibition of spinal glial activity as well as proinflammatory cytokine production.

Perspective

The present study may initiate a discussion on the possible roles of NT-3/glia/cytokines in the therapeutic effects of acupuncture and provide insight on the mechanism underlie the analgesic effects of acupuncture on pain associated with arthritis.     

Acupuncture analgesia in a new rat model of ankle sprain pain

The lack of suitable experimental animal models for persistent pain showing clear acupuncture analgesia, has been the major stumbling block in the investigation of the physiological mechanisms of acupuncture analgesia. The present study developed a new rat model of ankle sprain pain and the effect of electroacupuncture (EA) on this model was examined. A common source of persistent pain in humans is the lateral ankle sprain. To model this condition, the rat's right ankle was bent repeatedly, overextending lateral ligaments, for 4 min under halothane anesthesia. The rat subsequently showed swelling of the ankle and a reduced stepping force of the affected limb for the next several days. The reduced stepping force of the limb was presumably due to a painful ankle since systemic injection of morphine produced temporary improvement of weight bearing. EA was applied to the SI-6 acupuncture point on the contralateral forelimb for 30 min under halothane anesthesia. After the termination of EA, behavioral tests measuring stepping force were periodically conducted during the next 4h. EA produced a 40% recovery in the stepping force of the sprained foot lasting for at least 2h. The magnitude of this improvement was equivalent to that obtained after a systemic injection of 2mg/kg of morphine and this improvement of stepping pressure was interpreted as an analgesic effect. The analgesic effect was specific to the acupuncture point since (1). the analgesic effect on the ankle sprain pain model could not be mimicked by EA applied to a nearby point, LI-4 and (2). EA applied to the SI-6 point was not effective in the knee arthritis pain model. The analgesic effect could not be blocked by systemic injection of opioid antagonists naloxone or naltrexone. These data suggest that EA produces a potent analgesic effect on the ankle sprain pain model in the rat. This analgesic effect is produced by applying EA to a site remote from the painful area in a stimulus point-specific way. The present study provides a powerful experimental animal model that can be used for investigating the unique physiological mechanisms involved in acupuncture analgesia.     

Met-enkephalin and beta-endorphin are not involved in the analgesic action of transcutaneous vibratory stimulation.

Although the analgesic effects observed during the application of vibration may be attributable to neuronal inhibition of the pain pathways, this does not account for the fact that pain relief sometimes persists for a long time after the end of vibration treatment. Two experiments were carried out in order to determine whether pain relief might involve the release of endogenous opioids. In the first experiment, we studied the effects of injecting either a morphine antagonist, naloxone (0.4 mg), or a placebo, on the analgesia resulting from vibratory stimulation in 12 patients suffering from acute or chronic pain. In the second experiment, the Met-enkephalin and beta-endorphin levels were determined before and after 30 min vibratory stimulation in the cerebrospinal fluid of 8 patients suffering from chronic pain and 1 control subject, all of whom had been fitted with a ventriculo-peritoneal drain which made it possible to collect samples of cerebrospinal fluid painlessly. The results of these experiments show, on the one hand, that the effects of naloxone on the vibration-induced analgesia did not differ from those of the placebo and, on the other hand, that no increase in the Met-enkephalin or beta-endorphin levels occurred concomitantly with pain relief. It will therefore be necessary to investigate other mechanisms as possible means of explaining the post-vibratory analgesic effects.     

Endogenous Anandamide and Cannabinoid Receptor-2 Contribute to Electroacupuncture Analgesia in Rats

Acupuncture is widely used clinically to treat acute and chronic pain conditions, but the mechanisms underlying its effect are not fully understood. Although endocannabinoids are involved in modulation of nociception in animal models and in humans, their role in acupuncture analgesia has not been assessed. In this report, we determined the effect of electroacupuncture (EA) on the level of anandamide in the skin tissue and the role of cannabinoid CB1 and CB2 receptors in the analgesic effect of EA in an animal model of inflammatory pain. Inflammatory pain was induced by local injection of complete Freund's adjuvant (CFA) into the hind paw of rats. Thermal hyperalgesia was tested with a radiant heat stimulus, and mechanical allodynia was quantified with von Frey filaments. The anandamide concentration in the skin tissue was measured by using high-performance liquid chromatography. EA, applied to GB30 and GB34, at 2 and 100Hz significantly reduced thermal hyperalgesia and mechanical allodynia induced by CFA injection. Compared with the sham group, EA significantly increased the anandamide level in the inflamed skin tissue. Local pretreatment with a specific CB2 receptor antagonist, AM630, significantly attenuated the antinociceptive effect of EA. However, the effect of EA was not significantly altered by AM251, a selective CB1 receptor antagonist. These findings suggest that EA potentiates the local release of endogenous anandamide from inflamed tissues. Activation of peripheral CB2 receptors contributes to the analgesic effect of EA on inflammatory pain.PerspectiveThis study shows that electroacupuncture increases the anandamide level in inflammatory skin tissues, and CB2 receptors contribute to the analgesic effect of electroacupuncture in a rat model of inflammatory pain. This information improves our understanding of the mechanisms involved in the analgesic effect of acupuncture.     

基于fMRI技术探讨电针与手针中枢机制响应差异

目前功能磁共振技术在针刺（电针与手针）中枢机制研究取得了一定进展,但不同针刺参数及形式的刺激在大脑的响应不同。本文收集了“功能磁共振与针刺”相关的国内外文献,以针刺“刺激-响应”模式为切入点,对电针刺激量及电针与手针的的中枢响应差异作一初步的论述。结果表明,在功能磁共振技术观测中,不同电针参数存在不同的中枢响应机制,并应将多个参数联合研究;其次,电针与手针在传入途径、作用机制、靶点、临床疗效等方面存在差异,也有着各自的优势病种。      

Acupoint Stimulation With Diluted Bee Venom (Apipuncture) Potentiates the Analgesic Effect of Intrathecal Clonidine in the Rodent Formalin Test and in a Neuropathic Pain Model

Although intrathecal (i.t.) administration of the α₂-adrenoceptor agonist clonidine has a pronounced analgesic effect, the clinical use of clonidine is limited by its side effects. Previously, our laboratory has demonstrated that the subcutaneous injection of diluted bee venom (DBV) into an acupoint (termed apipuncture) produces significant analgesic effect in various pain animal models. The present study was designed to examine whether DBV injection into the Zusanli acupoint (ST-36) could enhance lower-dose clonidine-induced analgesic effects without the development of hypotension, bradycardia, or sedation. In the mouse formalin test, DBV injection produced a dramatic leftward shift in the dose-response curve for clonidine-induced analgesia. In a rat neuropathic pain model i.t. clonidine dose dependently suppressed chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia, and this clonidine-induced analgesic effect was significantly potentiated by apipuncture pretreatment. DBV apipuncture alone or in combination with a low dose of i.t. clonidine produced an analgesic effect similar to that of the high dose of clonidine, but without significant side effects. The analgesic effect produced by the combination of i.t. clonidine and apipuncture was completely blocked by pretreatment with an α₂-adrenoceptor antagonist. These data show that DBV-apipuncture significantly enhances clonidine-induced analgesia and suggest that a combination of low dose clonidine with acupuncture therapy represents a novel strategy for pain management that could eliminates clonidine's side effects.PerspectiveThis study demonstrated that intrathecal clonidine-induced analgesia is significantly enhanced when it is combined with chemical acupuncture treatment. The administration of low-dose clonidine in combination with acupuncture produced a potent analgesic effect without significant side effects and thus represents a potential novel strategy for the management of chronic pain.     

From Peripheral to Central: The Role of ERK Signaling Pathway in Acupuncture Analgesia

Despite accumulating evidence of the clinical effectiveness of acupuncture, its mechanism remains largely unclear. We assume that molecular signaling around the acupuncture needled area is essential for initiating the effect of acupuncture. To determine possible bio-candidates involved in the mechanisms of acupuncture and investigate the role of such bio-candidates in the analgesic effects of acupuncture, we conducted 2 stepwise experiments. First, a genome-wide microarray of the isolated skin layer at the GB34-equivalent acupoint of C57BL/6 mice 1 hour after acupuncture found that a total of 236 genes had changed and that extracellular signal–regulated kinase (ERK) activation was the most prominent bio-candidate. Second, in mouse pain models using formalin and complete Freund adjuvant, we found that acupuncture attenuated the nociceptive behavior and the mechanical allodynia; these effects were blocked when ERK cascade was interrupted by the mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) inhibitor U0126 (.8 μg/μL). Based on these results, we suggest that ERK phosphorylation following acupuncture needling is a biochemical hallmark initiating the effect of acupuncture including analgesia.PerspectiveThis article presents the novel evidence of the local molecular signaling in acupuncture analgesia by demonstrating that ERK activation in the skin layer contributes to the analgesic effect of acupuncture in a mouse pain model. This work improves our understanding of the scientific basis underlying acupuncture analgesia.     

Can electroacupuncture or transcutaneous nerve stimulation influence cognitive and emotional outcome after stroke?

OBJECTIVE: The authors know of no controlled randomized studies on the cognitive effects of acupuncture following stroke. The aim of this study is to assess the effects of acupuncture combined with electroacupuncture and transcutaneous electrical nerve stimulation on emotional and cognitive functioning. METHODS: Five to 10 days after stroke, 54 patients with moderate or severe functional impairment were randomized to 1 of 3 interventions: (i) acupuncture, including electroacupuncture; (ii) sensory stimulation with high-intensity, low-frequency transcutaneous electrical nerve stimulation that induced muscle contractions; and (iii) low-intensity (subliminal) high-frequency transcutaneous electrical nerve stimulation (control group). Twenty treatment sessions were performed over 10 weeks. Outcome measures included cognitive performance and emotional functioning. Measures were obtained prior to any stimulation treatment and at 3 and 12 months. RESULTS: At baseline, groups were comparable with regard to demographic, medical, emotional and functional status. The control group demonstrated lower cognitive performances, but this difference did not remain at 3 or 12 months. There were no treatment effects on emotional status. When pooling treatment groups, there were significant cognitive and emotional improvements. CONCLUSION: Although patients from all 3 groups demonstrated cognitive and emotional improvements, the present study does not suggest any treatment effects on emotional status or cognitive functioning.     

Acupuncture for the relief of cancer-related pain--a systematic review.

AIMS: This systematic review summarises the existing evidence on acupuncture for cancer-related pain. METHODS: Literature searches were conducted in seven databases. All clinical studies of acupuncture, electroacupuncture and ear acupuncture in cancer patients with the main outcome measure of pain were included. Data were extracted according to pre-defined criteria by two independent reviewers and methodological quality was assessed using the Jadad scale. RESULTS: Of the seven studies included, one high quality randomised clinical trial of ear acupuncture showed statistically significant pain relief in comparison with placebo ear acupuncture. All the other studies were either non-blinded (n=2) or uncontrolled clinical trials (n=4). Most investigations suffered from methodological flaws such as inadequate study design, poor reporting of results, small sample size and overestimation of the results. CONCLUSIONS: The notion that acupuncture may be an effective analgesic adjunctive method for cancer patients is not supported by the data currently available from the majority of rigorous clinical trials. Because of its widespread acceptance, appropriately powered RCTs are needed.     

The role of corticotropin-releasing factor in pain and analgesia

Corticotropin-releasing factor (CRF) is a peptide that is released from the hypothalamus and in widespread areas of the brain following exposure to stressors. It is considered to be a mediator of many of the effects of stress, and its analgesic properties have been demonstrated in many studies. However, for primarily methodological reasons, the effects of CRF in the central nervous system have been neglected whereas the peripheral effects of CRF have been overemphasized. We present evidence that: (1) CRF can act at all levels of the neuraxis to produce analgesia; (2) the release of beta-endorphin does not explain the analgesia following intravenous or intracranial CRF administration; (3) inflammation must be present for local CRF to evoke analgesia and (4) the analgesic effects of CRF show specificity for prolonged pain. These findings suggest that CRF may have a significant role in chronic pain syndromes associated with hypothalamic-pituitary-adrenal axis abnormalities. Furthermore, CRF may represent a new class of analgesics that merits further study. Implications for the relationship between stress and pain are discussed.     

Dental analgesia produced by non-painful low-frequency stimulation is not influenced by stress or reversed by naloxone

The dental pain threshold elevation produced by non-painful, low-frequency transcutaneous electrical nerve stimulation (TENS) in healthy humans was not reduced by the administration of 0.8 mg of naloxone i.v. Neither ACTH, prolactin nor growth hormone (GH) release were related to the pain threshold elevations. The present study indicates that the dental pain threshold elevation during non-painful, low-frequency TENS is not based on the same opioid-dependent mechanisms as the dental pain threshold elevation during acupuncture or the clinical analgesia during low-frequency TENS. Stress or other adenohypophyseal mechanisms involving ACTH, prolactin or GH do not explain the analgesia induced by non-painful, low-frequency TENS.     

Dynorphin: important mediator for electroacupuncture analgesia in the spinal cord of the rabbit

Intrathecal injection of 12 nmol of dynorphin elicited marked analgesia as measured by tail flick latency, the effect being about 20 times more potent than with morphine. This analgesic effect could be reversed by naloxone at a dose 1.5-fold higher than that needed to reverse morphine analgesia. Intrathecal injection of anti-dynorphin antibody blocked electroacupuncture (EA) analgesia by 77%, the effect lasting for at least 4 h. In rabbits made tolerant to EA analgesia by long-term EA stimulation, intrathecal injection of dynorphin no longer exhibited an analgesic effect. No analgesia was noticed when dynorphin (10 nmol) was injected into the periaqueductal grey (PAG) of the rabbit, nor was EA analgesia blocked by anti-dynorphin antibody injected into PAG. These results suggest that dynorphin reduces nocifensive responses in the spinal cord and may play an important role in mediating EA analgesia at the spinal level.     

异博定和氯化钙对电针镇痛效果及小鼠脑细胞游离钙镁浓度的影响

目的 :进一步探讨针刺镇痛机理。方法 :用离子探针Fura -2 -AM和Furaptra -AM配合高敏度AR -CM -MIC阳离子测定系统分别测定了异博定和氯化钙对电针的镇痛效果及小鼠下丘脑 (HT)和导水管周围灰质区 (PAG)细胞内游离钙离子浓度 ( [Ca2 +]i )及游离镁离子浓度 ( [Mg2 +]i )的变化。结果 :电针小鼠拟“人中”、“承浆”穴 ,上述两脑区 [Ca2 +]i均明显降低 ,而 [Mg2 +]i则略有升高 ,[Ca2 +]i/[Mg2 +]i比值明显降低 ;小鼠脑室内注射少量CaCl2 及腹腔注射钙通道阻断剂异博定(verapamil)均可抑制电针的镇痛效应。结论 :电针镇痛效果可能与细胞内的游离钙镁离子浓度比值有关。     

中脑导水管周围灰质内催产素对痛阈和电针镇痛效应的影响

本工作以钾离子透入法引起大鼠甩尾反应的电流强度（ｍＡ）为痛反应指标，观察了中脑导水管周围灰质（ＰＡＧ）腹外侧区注射催产素（ＯＴ）和抗催产素血清（ＡＯＴＳ）对大鼠痛阈和电针镇痛效应的影响。结果表明，ＰＡＧ注射ＯＴ能增加大鼠痛阈和电针镇痛效应；注射ＡＯＴＳ以中和内源性的ＯＴ后，对大鼠痛阈虽克明显影响，但能显著降低电针期的停针后的电针镇痛效应。提示ＰＡＧ内生理水平的ＯＴ在电针镇痛中发挥一定作用。