Elsevier

Progress in Neurobiology

Volume 85, Issue 4, August 2008, Pages 355-375
Progress in Neurobiology

Neural mechanism underlying acupuncture analgesia

https://doi.org/10.1016/j.pneurobio.2008.05.004Get rights and content

Abstract

Acupuncture has been accepted to effectively treat chronic pain by inserting needles into the specific “acupuncture points” (acupoints) on the patient's body. During the last decades, our understanding of how the brain processes acupuncture analgesia has undergone considerable development. Acupuncture analgesia is manifested only when the intricate feeling (soreness, numbness, heaviness and distension) of acupuncture in patients occurs following acupuncture manipulation. Manual acupuncture (MA) is the insertion of an acupuncture needle into acupoint followed by the twisting of the needle up and down by hand. In MA, all types of afferent fibers (Aβ, Aδ and C) are activated. In electrical acupuncture (EA), a stimulating current via the inserted needle is delivered to acupoints. Electrical current intense enough to excite Aβ- and part of Aδ-fibers can induce an analgesic effect. Acupuncture signals ascend mainly through the spinal ventrolateral funiculus to the brain. Many brain nuclei composing a complicated network are involved in processing acupuncture analgesia, including the nucleus raphe magnus (NRM), periaqueductal grey (PAG), locus coeruleus, arcuate nucleus (Arc), preoptic area, nucleus submedius, habenular nucleus, accumbens nucleus, caudate nucleus, septal area, amygdale, etc. Acupuncture analgesia is essentially a manifestation of integrative processes at different levels in the CNS between afferent impulses from pain regions and impulses from acupoints. In the last decade, profound studies on neural mechanisms underlying acupuncture analgesia predominately focus on cellular and molecular substrate and functional brain imaging and have developed rapidly. Diverse signal molecules contribute to mediating acupuncture analgesia, such as opioid peptides (μ-, δ- and κ-receptors), glutamate (NMDA and AMPA/KA receptors), 5-hydroxytryptamine, and cholecystokinin octapeptide. Among these, the opioid peptides and their receptors in Arc-PAG-NRM-spinal dorsal horn pathway play a pivotal role in mediating acupuncture analgesia. The release of opioid peptides evoked by electroacupuncture is frequency-dependent. EA at 2 and 100 Hz produces release of enkephalin and dynorphin in the spinal cord, respectively. CCK-8 antagonizes acupuncture analgesia. The individual differences of acupuncture analgesia are associated with inherited genetic factors and the density of CCK receptors. The brain regions associated with acupuncture analgesia identified in animal experiments were confirmed and further explored in the human brain by means of functional imaging. EA analgesia is likely associated with its counter-regulation to spinal glial activation. PTX-sesntive Gi/o protein- and MAP kinase-mediated signal pathways as well as the downstream events NF-κB, c-fos and c-jun play important roles in EA analgesia.

Introduction

Acupuncture has been a healing art in traditional Chinese medicine for more than 2000 years. Various disorders can effectively be cured by inserting long, fine needles into specific “acupuncture points” (acupoints) on the skin of the patient's body. Besides China, acupuncture has spread to over 160 countries and regions. The World Health Organization recommends the use of acupuncture treatment for 43 diseases. Since acupuncture was proposed by NIH consensus as a therapeutic intervention of complementary medicine (NIH, 1997), acupuncture efficacy has become more accepted in the Western world.

Among acupuncture therapies, the acupuncture-induced analgesic effect has been used widely to alleviate diverse pains, particularly chronic pain, and is termed “acupuncture analgesia.” Considering the clinical therapy of acupuncture, it is inevitable that psychological factors are involved in the analgesia. Whether acupuncture analgesia has a physiological basis or is simply attributable to hypnosis or other psychological effects has long been a focus of argument. Consequently, increasing attention has been paid to exploring the physiological and biochemical mechanisms underlying acupuncture analgesia, particularly the brain mechanisms. In the past decades, our understanding of how the brain processes signals induced by acupuncture has developed rapidly (Cao, 2002, Carlsson, 2001, Chang, 1973, Chang, 1980, Chung, 1989, Han and Terenius, 1982, Han, 1986, Han, 1989, Han, 2003, Le Bars and Willer, 2002, Mayer, 2000, Pomeranz, 2001, Sims, 1997, Staud and Price, 2006, Takeshige, 1989, Vincent and Richardson, 1986, Ulett, 1989, Ulett et al., 1998, Wang et al., 2008). This review focuses on the neuronal mechanisms of acupuncture analgesia. On the basis of the data obtained in the last decades and the use of multidisciplinary new techniques, more studies on neural mechanisms underlying acupuncture analgesia are predominately interested in cellular and molecular substrate and functional brain imaging during the last 10 years. The main advancements are: (1) individual differences of acupuncture analgesia are associated with inherited genetic factors and the density of CCK receptors (Chae et al., 2006, Lee et al., 2002, Wan et al., 2001). (2) The brain regions associated with acupuncture analgesia identified in animal experiments were confirmed and further explored in the human brain by means of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) (see Section 3.5). Some brain regions were activated and de-activated, when acupuntrue treatment evoked acupuncture feeling “De-Qi” associated with the efficiency of acupuncture analgesia (see Section 1.1). (3) Frequency-dependent EA analgesia is mediated by the different opioid receptor subtypes (see Section 4.1.2). (4) Both CCK release and the density of CCK receptors are closely associated with individual sensitivity to acupuncture. (5) EA and NMDA or AMPA/KA receptor antagonists have a synergic anti-nociceptive action against inflammatory pain. (6) EA and disrupting glial function synergistically suppress inflammatory pain. EA analgesia is likely associated with its counter-regulation to spinal glial activation (see Section 5.1). (7) PTX-sesntive Gi/o protein-, opioid receptor- and MAP kinase-mediated signal pathways as well as the downstream events NF-κB, c-fos and c-jun play important roles in EA analgesia (see Section 5.2).

The acupoints used by acupuncturists are based on the ancient meridian theory, in which the meridians are referred to as channels “Jing” and their branches “Luo,” where 361 acupoints are located. The meridians are considered as a network system to link acupoints via so-called “Qi” (energy) streaming in the meridians. On the basis of this theory, traditional acupuncturists deem that pain is attributed to a disease-induced blockade of meridians. Therefore, when the blockade is purged by acupuncture, this elicits the smooth streaming of “Qi” in the meridians, and pain is alleviated. However, no convincing evidence shows the existence of novel structures serving as the anatomical foundations of meridians, although related studies have been carried out. Given that the meridian theory has been effectively used for treatment in traditional Chinese medicine, it is conceivable that the meridians might be a functional, but not an anatomical, concept that includes a summation of multiple physiological functions, including the nervous, circulatory, endocrine and immune systems. It is well known that the concept of the constellation has played an important role in astronomy and navigation for a long time. The meridian system might resemble the concept of the constellation in which fictive lines (channels) link various stars (acupoints).

Traditional acupuncturists remarkably emphasize “needling feeling” in clinical practice. It seems that acupuncture analgesia is manifest only when an intricate feeling occurs in patients following manipulation of acupuncture (Hui et al., 2005, Haker and Lundeberg, 1990, Pomeranz, 1989). This special feeling is described as soreness, numbness, heaviness and distension in the deep tissue beneath the acupuncture point. In parallel, there is a local feeling in the acupuncturist's fingers, the so-called “De-Qi.” The acupuncturist feels pulling and increased resistance to further movement of the inserted needle, which is similar to that of a fisherman when a fish takes the bait (Kong et al., 2005, Langevin et al., 2001, MacPherson and Asghar, 2006). A clinical observation showed that acupuncture needles inserted into the lower limbs fail to produce this “De-Qi” feeling or have any analgesic effect on the upper part of the body in paraplegic patients (Cao, 2002). Consequently, great attention was first paid to the involvement of somatic sensory functions of the nervous system in acupuncture analgesia and the innervation of acupoints. There are a total of 361 acupoints on the skin of the human body. In the 1970s, an elegant morphological study showed the topographical relationships between 324 acupoints of 12 meridians as well as the Ren meridian (Zhou et al., 1979, Zhou et al., in press). By means of opography, they observed the innervation of the different tissues underneath acupoints, including epidermis, dermis, subcutaneous tissue, muscle and tendon organs in 8 adult cadavers, 49 detached extremities and 24 lower extremities. It was found that out of 324 acupoints located on the meridians, 323 exhibited rich innervation mainly in the deep tissues, clearly indicating that the acupoints on all of the meridians were innervated by peripheral nerves. A recent study indicated a significantly decreased number and density of subcutaneous nerve structures compared with non-acupoints in human (Wick et al., 2007). Unfortunately, their observation was limited only to the acupoints on the skin. It has demonstrated that afferent fibers innervating the skin are not important in mediating acupuncture signals (Chiang et al., 1973, Han et al., 1983, Shen et al., 1973).

To further trace the innervation of acupoints, a recent study explored the distribution of afferent nerve endings with acupoints in the rat hindlimb, in light of the fact that the location of these acupoints are anatomically identical to those of humans (Li et al., 2004). By combining single fiber recordings with Evans blue extravasation, the location of the receptive fields (RFs) for each identified unit recorded was marked on scaled diagrams of the hindlimb. Noxious antidromic stimulation-induced Evans blue extravasation was used to map the RFs of C-fibers in the skin or muscles. The RFs were concentrated either at the sites of acupoints or along the orbit of meridian channels, indicating that the distribution of RFs for both A- and C-fibers is closely associated with acupoints. Similarly, the majority of deep sensory receptors are located at acupoints in muscle. Therefore, authors assumed that acupoints in humans may be excitable muscle/skin-nerve complexes with a high density of nerve endings (Li et al., 2004).

  • (1)

    Two acupuncture manipulations are clinically used: manual manipulation (MA) and electrical acupuncture (EA). In MA, the acupuncture needle is inserted into the acupoint and twisted up and down by hand; this is commonly used by traditional acupuncturists. In EA, stimulating current is delivered to acupoints via the needles connected to an electrical stimulator. Instead of insertion of acupuncture needles, a surface electrode on the skin over the acupoint is also described as EA. But it is different from transcutaneous electrical nerve stimulation (TENS). The surface electrodes of TENS are delivered on the skin of pain region rather than acupoints.

  • (2)

    The acupuncture-induced intricate feeling (soreness, numbness, heaviness and distension) in the deep tissue beneath the acupoint is essential to acupuncture analgesia.

  • (3)

    Following the application of acupuncture, the pain threshold gradually increases in both humans and animals, indicating a delayed development of acupuncture analgesia. Moreover, there is a long-lasting analgesic effect after acupuncture stimulation is terminated (Cui et al., 2005, Chiang et al., 1973, Han et al., 1983, Mayer et al., 1977, Pomeranz and Chiu, 1976, Research Group, 1973). The pain threshold to potassium iontophoresis at eight points distributed on the head, thorax, back, abdomen and leg was fairly stable during a period of over 100 min in volunteers. Acupuncture manipulation at the “Hegu” acupoint (LI-4) gradually produced an increase in pain threshold with a peak increase occurring 20–40 min after needle insertion, and persisted over 30 min after withdrawal of the needle. Injection of 2% procaine into LI-4 just prior to acupuncture produced neither local sensation nor an analgesic effect (Fig. 1) (Chiang et al., 1973, Farber et al., 1997, Han et al., 1983, Research Group, 1973). In a recent study on healthy subjects, baseline thermal thresholds (cold and warm sensations and cold and hot pain) were measured at the medial aspects of both lower extremities. Five seconds of hot pain (HP) was delivered to the testing sites and the corresponding pain visual analog scale (VAS) scores were recorded. Thirty seconds of EA (5 Hz, 6 V) was delivered via “Yinbai” (SP1) and “Dadun” (LR1) on the left lower extremities. The warm thresholds of both medial calves significantly increased (p < 0.01), whereas the VAS scores of the acute thermal pain threshold were reduced significantly at the ipsilateral calf during electrical acupuncture in comparison to pre-acupuncture and post-acupuncture (p < 0.01) measurements, suggesting that EA has an inhibitory effect on C-fiber afferents and the analgesic benefit observed is most likely Aδ afferent-mediated (Leung et al., 2005).

  • (4)

    The analgesic effect of acupuncture is characterized by clear individual differences. In a study comparing the analgesic effects of three acupuncture modes (manual, electroacupuncture, and placebo) in healthy subjects, acupuncture treatment, but not placebo, lowered pain ratings in response to calibrated noxious thermal stimuli. Highly significant analgesia was found in 5 of the 11 subjects. Of the five responders, two responded only to electroacupuncture and three only to manual acupuncture, suggesting that acupuncture's analgesic effects on experimental pain may depend on both subject and mode (Kong et al., 2005). In addition, a role of inherited genetic factors in the individual differences of acupuncture analgesia was reported (Chae et al., 2006, Lee et al., 2002).

The existence of psychological factors in acupuncture analgesia when treating a patient's chronic pain is not unexpected, as with many medical treatments (Price et al., 1984). But increasing evidence demonstrates that acupuncture analgesia is predominately attributable to its physiological rather than psychological action despite a high skepticism (Ezzo et al., 2000, Lee and Ernst, 2005, Lundeberg and Stener-Victorin, 2002). Clinical observations have shown that acupuncture analgesia is very effective in treating chronic pain, helping from 50% to 85% of patients (compared to morphine which helps only 30%). Furthermore, acupuncture analgesia is better than placebo in patients (Lewith and Machin, 1983, Richardson and Vincent, 1986) and in normal volunteers (Lee and Ernst, 1989, Ulett, 1989). In support of these early results, recent studies provide new evidence for physiological actions of acupuncture (Bausell et al., 2005, Pariente et al., 2005). In 14 patients suffering from painful osteoarthritis scanned with PET, it was found that the insula ipsilateral to the site of acupuncture needling was activated to a greater extent during acupuncture than during the placebo intervention. Acupuncture and placebo (with the same expectation of effect as acupuncture) caused greater activation than skin prick (no expectation of a therapeutic effect) in the right dorsolateral prefrontal cortex, anterior cingulate cortex, and midbrain (Pariente et al., 2005). Stimulation of the hypothalamo–pituitary axis (HPA) resulting in adrenocorticotropic hormone (ACTH) secretion occurs in response to a great variety of psychological or physical stressors. In deeply anaesthetized rats, EA enhanced ATCH plasma release and up-regulated expression of Fos in the hypothalamic–pituitary corticotrope axis without usual autonomic responses to psychological stress, such as tachycardia or blood pressure elevation, which was blocked by deprivation of nociceptive primary afferent input using neonatal capsaicin. (Pan et al., 1996, Pan et al., 1997). In the awaking rat, immobilization stress predominantly is a psychological stressor. Further results showed that immobilization stress-induced ATCH release and Fos expression were not changed by capsaicin treatment. These findings suggest that EA depends on the physiological afferent signal elicited in the somatosensory pathway. Taken together, it is reasonable that acupuncture has specific physiological effects and that patients’ expectation and belief regarding a potentially beneficial treatment modulate activity in the hypothalamic–pituitary corticotrope system.

Section snippets

Acupuncture-induced the “De-Qi” feeling

In clinical practice, traditional acupuncturists remarkably emphasize “De-Qi” feeling, including a characteristic needling sensation in the patient and the finger feeling of the acupuncturist, suggesting that efficacy of acupuncture analgesia closely depends upon the “De-Qi” (Hui et al., 2005, Haker and Lundeberg, 1990, Pomeranz, 1989, Wang et al., 1985). To address these reactions to acupuncture needling may be a stepping-stone to understanding the mechanism of acupuncture analgesia.

Acupuncture analgesia as a result of sensory interaction

One of traits of acupuncture analgesia is that it lasts long after the cessation of the needling stimulation, suggesting the involvement of central summation. In general, pain can be alleviated by various procedures, such as acupuncture, forceful pressure, vibration and heating as well as white noise and flicker. Consequently, it is considered that one kind of sensation may be suppressed by another kind. It is well known that many areas in the CNS, particularly the reticular formation, receive

Roles of transmitters and modulators in acupuncture analgesia

In the early ‘70s, an elegant study from Han's group revealed that when the cerebrospinal fluid of donor rabbits given acupuncture was infused into the cerebral ventricles of recipient rabbits, the pain threshold of recipients was increased, strongly suggesting the involvement of central chemical mediators in acupuncture analgesia (Research Group, 1974). From then on, many findings in human and animal studies have demonstrated that acupuncture analgesia is a complex physiological process

Glial function in acupuncture analgesia

Increasing evidence has revealed that spinal cord glia (microglia and astrocytes) make important contributions to the development and maintenance of inflammatory and neuropathic pain (Deleo et al., 2004, Ledeboer et al., 2005, Ma and Zhao, 2002, Song and Zhao, 2001, Sun et al., 2007a, Watkins et al., 2005, Watkins et al., 2007, Zhang et al., 2005c, Zhang et al., 2007c). Also, recent studies found that spinal glia has an intimate relationship with EA analgesia (Kang et al., 2007, Sun et al., 2006

Conclusions and consideration

Acupuncture, an age-old healing art, has been accepted to effectively treat various diseases, particularly chronic pain. Despite the involvement of psychological factors in acupuncture treatment of patients and stress in animal behavioral tests, a large volume of evidence clearly demonstrates that acupuncture analgesia has physiological, anatomical and neurochemical bases.

  • (1)

    Acupuncture analgesia is manifest only when the intricate feeling of acupuncture (soreness, numbness, heaviness and

Acknowledgements

The author wishes to thank Prof. Cao for her critical reading of the manuscript and Mr. D. Zhou for helping with making figures. This work was supported by grants from the National Basic Research Program (No. 2007CB5125 and 2006CB500807) of China.

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