Overview of reported transcutaneous electrical acupoint stimulation effects on pain mediators

Deng Kai-feng (邓凯烽), Chen Ri-lan (陈日兰), Liao Zi-long (廖子龙), Wang Guo-xiang (汪国翔), Zhu Ying (朱英)

1 Graduate School of Guangxi University of Traditional Chinese Medicine, Nanning 530001, China

2 Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning 530011, China

Abstract

Keywords: Transcutaneous Electrical Nerve Stimulation; Acupoint Therapy; Pain; Analgesia; Mechanism; Review

Transcutaneous electrical acupoint stimulation (TEAS) is a combination of the transcutaneous electrical nerve stimulation (TENS) in physical medicine and acupoints in traditional Chinese medicine acupuncture therapy. It is a new treatment method by stimulating the meridian system to improve the functionin vivo,when the microcurrent is passed into the human body through the acupoint surface skin[1-2]. Many studies have pointed out that TEAS clears lactic acid, raises hemoglobin, scavenges oxygen free radicals, and regulates the metabolism of blood glucose and amino acid, which effectively improve the athletic ability[3-6]. Therefore, it is widely used in athletes. In recent years, the long-term drug treatment of the high-incidence pain syndrome has not only caused serious adverse reactions, but also brought huge economic pressure to patients. Meanwhile, repeated attacks of pain syndrome seriously affect the patients’ quality of life. Because of its painless and non-invasive advantages, TEAS has been widely used in the treatment of pain syndrome. Many studies have shown that TEAS can treat the postoperative, postpartum, chronic, and cancer pain, as well as other pain diseases[7-11]. Here, we searched the online databases, including China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (WF), China Science and Technology Journal Database (CSTJ) and PubMed to screen relevant literatures on TEAS intervention in pain syndrome. We further reviewed and summarized the analgesic mechanism, the effects on pain mediators, and the current weaknesses of TEAS based on the retrieved literatures.

1 Analgesic Mechanism of TEAS

1.1 Gate control theory

The gate control theory[12]was jointly proposed by Canadian psychologist Melzack R and British physiologist Wall PD. The theoretical mechanism is that the gliocytes in the cornu dorsale medullae spinalis have a gate-like control mechanism for the second-level neuron T cells in the cornu dorsale medullae spinalis, which plays a gate-like control effect on the pain stimulus transmitting into the T cells, thus inhibiting pain. In recent years, the gate control mechanism for the pain transmission pathway has been further developed. Lu Y,et al[13]identified a glycine-gate- controlled pre-gate-feedback inhibition system that separates the tactile and the pain transmission pathways in the cornu dorsale medullae spinalis. Duan B,et al[14]investigated the transmission and gate loops of mechanical pain in the pain transmission pathway with the transgenic identification technology, and revealed that it was composed of the peripheral nociceptors and mechanoreceptors, the medullispinal excitatory somatostatin and dynorphin inhibitory neurons.

1.2 Theory of endogenous opioid peptide release

Following the gate control theory, the mechanism of acupuncture analgesia has been investigated in China. Academician Han Ji-sheng is one of the founders of this theory. In the 1980s, based on the results of animal experiments, academician Han JS and his research team firstly identified that the low-frequency (2 Hz) electroacupuncture (EA) stimulation increased endorphins from the brain and enkephalins from the spinal cord[15]; while the high-frequency (100 Hz) EA stimulation promoted the dynorphin release from the spinal cord[16]. They also found that the sparse-dense wave (2 Hz/100 Hz) stimulated the simultaneous release of the above three opioid peptides to produce a synergistic analgesic effect[17].

2 Effect of TEAS on Pain Mediators

2.1 Prostaglandin (PG)

PG is a type of strong inflammatory and pain mediator. Prostaglandin E2(PGE2) is more potent to pain hypersensitivity, as well as to spontaneous pain by directly stimulating the fibers[18]. PG also induces the inflammatory cell aggregation, accelerates the inflammatory response, increases the inflammatory and analgesic effects of other inflammatory mediators, as well as aggravates the pain level. PG is produced by the arachidonic acid under the cyclooxygenase (COX)-2 catalysis during inflammation. COX is a key enzyme for arachidonic acid to metabolize and synthesize the PG. At present, two isozyme subtypes of COX-1 and COX-2 have been identified. Studies have shown that TEAS relieves dysmenorrhea by stimulating the release of PG and cortisol (Cor)[19]. Studies have also shown that TEAS down-regulates the level of peripheral serum pain-causing substance PGE2, up-regulates the level of central cerebrospinal fluid analgesic substance β-endorphin, and maintains the level of the cholecystokinin-octapeptide (the anti-opioid peptide pain maintenance substance), thus to simultaneously prevent and treat the orthodontic toothache with the peripheral and central approaches[20].

2.2 5-hydroxytryptamine (5-HT)

5-HT, also known as serotonin, is involved in hyperalgesia formation and is a strong pain-causing neurotransmitter[21-22]. The distribution of 5-HT is 99% in the periphery, and only 1% in the central nervous system. As a neuroactive substance involved in analgesia in the central system, and an important inflammatory factor mediating pain in the periphery, 5-HT plays an important role in transmitting and regulating the noxious information mediated by different receptors. 5-HT1Ain the periphery mainly mediates the pain. The mechanism may be regulating the primary afferent terminals and the release of peripheral nerve terminals substance P (SP), glutamate and galanin (GAL) via the 5-HT1Areceptor subtypes, thereby regulating the peripheral pain information transmission. In the central nervous system, the analgesic effect of 5-HT is achieved by activating 5-HT1Areceptors in the raphe nucleus. The analgesic mechanism of 5-HT2Areceptors in the central nervous system is to produce synaptic inhibition by reducing the release of γ-aminobutyric acid (GABA) from spinal cord inhibitory neurons. The pain-causing effect may be the painful neuron excitement by activating the protein kinase C (PKC) pathway to produce continuous calcium influx. Studies have shown that 5-HT5Areceptor is involved in the regulatory process of inhibiting astrocyte activation and chemotherapy pain, which reduces the chemotherapy-caused pain[23]. Studies have confirmed that TEAS raises the 5-HT levels in the cerebral cortex and the brainstem by activating the brain neurons, while down-regulates the 5-HT level in the local inflammatory regions, thereby alleviating the pain[24].

2.3 Interleukin (IL)

Many IL subtypes have been currently identified, including the main pro-inflammatory factor IL-1β, and the anti-inflammatory cytokines IL-4, IL-8 and IL-10. IL-1β is one of the earliest discovered pain related cytokines caused by peripheral nerve injury, playing an important role in chronic pain after surgery. Both IL-4 and IL-10 produce anti-inflammatory effects by binding to their own receptors, to activate the Janus kinase/signaling and transcription activator signaling pathways, thereby reducing the activity of nuclear factor-KB and inhibiting the release of pro-inflammatory cytokines such as IL-1β[25]. IL-8 and IL-10 are important pro-inflammatory factors involved in postoperative inflammatory response. The plasma concentrations of IL-8 and IL-10 are positively correlated with the degree of injury. IL-8 regulates pain mainly by changing cytokine-mediated release of pain transmitters. IL-10 is mainly derived from the spinal cord glial cells (microglia, astrocytes), and can also be synthesized and secreted by various immune cells such as monocytes, macrophages, and T helper cells, playing an important immunomodulatory role during the incidence and development of tumors. IL-10 inhibits the release of pro-inflammatory factors IL-8 and tumor necrosis factor-α (TNF-α) at the transcriptional level, and can also promote the release of some natural anti-inflammatory factors, thereby weakening the functions of the pro-inflammatory factors[26-27]. IL-1, IL-6 and IL-10 play central roles in the early stage of inflammation. The elevated IL-6 level reflects the tissue damage degree, thus having become the main monitoring indicator of the traumatic stress degree. Studies have confirmed that TEAS, applied during surgery, improves gastrointestinal function and reduces the incidence of postoperative pain, vomiting and other complications by regulating the postoperative blood IL-6 level[28-29]; reduces the use of anesthetics and enhances the immune function of lung cancer patients during the perioperative period[30]; also improves the cognitive function and relieves the depression by regulating the release of IL-1β and IL-6[31]. Wang JL,et al[32]demonstrated that TEAS down-regulated the IL-6 level in the early stage of cerebral ischemia and increased the IL-6 level during the recovery period. However, its role in the central nervous system and various phases of ischemic brain injury has not been well understood, and further research is necessary.

2.4 SP

SP is a common nociceptive stimulating neuropeptide, widely distributed in the central and peripheral nervous systems[33]and transmitting pain signals to induce pain. The pain-causing mechanisms mainly include two aspects, one is to increase the excitability and decrease the pain threshold by changing the chemical environment around nociceptors; the other is to interact with the cell membrane receptors of lymphocytes, monocytes, macrophages, neutrophils, and mast cells to induce the release of cytokines such as IL-1, IL-6, and TNF-α for inflammation stimulation[34]. Studies have reported that TEAS achieves the analgesic effects through the central pathway by regulating the SP level[35].

2.5 TNF-α

TNF-α is an inflammation-initiating factor mainly produced by macrophages and monocytes. It is closely related to the neuropathic pain and plays an important role in the early stage of inflammation and injury with diversity and complexity[36-37]. TNF-α up-regulates the number and molecule expression of glial cells to release many inflammatory cytokines, leading to increased pain; produces thermal and mechanical hyperalgesia by enhancing the sensitivity of spinal dorsal horn neurons. Many studies in China have found that TEAS plays an analgesic function by decreasing TNF-α release to improve the inflammatory status and signal pathways, thereby reducing the inflammatory damage of central neurons[38-40].

3 Summary

TEAS is a safe and effective treatment technique to achieve the analgesic effect by interfering in the release of related pain mediators and affecting the pain transmission. The pain mediators, playing major roles during injury and pain, include PGE2, IL-1β, SP, TNF-α, 5-HT, etc., while the analgesic mediators include IL-4, IL-8 and IL-10. As a class of strong pain mediator, PGE2increases the pain-causing effect of other inflammatory mediators. IL-10 achieves the analgesic effect by inhibiting the release of pro-inflammatory factors, and promoting the release of some natural anti-inflammatory factors. 5-HT can not only induce pain but also relieve pain. 5-HT in the peripheral tissues strongly induces pain, while in the central system mainly inhibits the pain occurrence. Different subtypes of IL play different roles in the process of pain. TNF-α mainly plays an important role in the early stage of inflammation. IL-1β plays an important role in chronic postoperative pain. Existing studies have confirmed the analgesic effect of TEAS by detecting 5-HT, SP, PGE2, IL, and so on. It can be seen that both pro-inflammatory factors and anti-inflammatory factors are secreted during pain. We believe that future research may start with the specific inflammatory factors, to further explore the conduction pathway and the strength of secreting inflammatory factors of TEAS.

The clinical advantages of TEAS are that different parameter combinations can be specifically selected, and acupoints can be selected according to different diseases and pain symptoms of patients, which provide more effective treatment method for improving patient symptoms and quality of life. However, the efficacy of TEAS for pain syndrome is also affected by stimulation parameters. The current research on the factors affecting the TEAS efficacy is mainly focused on the stimulation parameters, such as the stimulation intensity, stimulation time, waveform, and frequency. The sparse-dense wave stimulation has not yet been widely applied according to the recent literatures, though the current academic and clinical researches have confirmed that it is more effective in delaying the treatment-related tolerance development versus the low-frequency or high-frequency stimulation alone[41]. Simultaneously, the parameters are not uniformly selected even if the same experimental design is used in some reported studies. Therefore, in recent years, some scholars have proposed that the TEAS parameters need to be quantified. Standardized electrical stimulation parameters, or identified repetitive electrical stimulation parameter strategies in single-parameter research model, will benefit the studies on more comparable clinical treatment mechanisms of TEAS in the future. This will not only provide a unified objective standard for experimental research, but also offer a theoretical basis for choosing the best TEAS parameters in clinical practice.

To treat the pain syndrome with TEAS, acupoints along the meridian, acupoints on the same-name meridians, acupoints on the interiorly-exteriorly paired meridians, and Ashi points are selected in most situations. The acupoint selection principles for different diseases are different, based on the overall concept of traditional Chinese medicine, even the experience in some studies. The reasons for acupoint selection have not been clearly discussed and have no clear mechanism research basis. Acupoint-selection pattern may be different even for the same disease, making the research scope unclear. Presently, few clinical literatures have reported the differences in the efficacy of electrical stimulation to different acupoints. Undeniably, most of the existing clinical studies have shown significant effects. However, the lack of multi- center large-sample parallel-controlled randomized controlled trials has somehow reduced the credibility.

How to optimize the electrical stimulation parameters, how to standardize the acupoint selection, and how to provide the reliable and convincing research evidences will be the main direction of the clinical research on TEAS. There is a long way to go for applying the TEAS in clinical practice better.

Conflict of Interest

The authors declare that there is no conflict of interest.

Acknowledgments

This work was supported by National Natural Science Foundation of China (国家自然科学基金, No. 81960908).

Received: 3 January 2020/Accepted: 16 April 2020