MA Cui (馬翠), ZOU Yichun (鄒依純), YE Yujuan (葉鈺娟), CAO Mengqi (曹夢(mèng)琪), YAN Xingke (嚴(yán)興科)

Acupuncture and Massage College of Gansu University of Chinese Medicine, Lanzhou 730000, China

Abstract Pain is a complex physiological and psychological activity, involving at least three dimensions, including pain sensation,pain emotion, and pain cognition. Acupuncture can clearly relieve the pain sensation of patients and improve pain emotion and pain cognition induced by pain; acupuncture participates in the multi-dimensional regulation of pain through brain regions of the limbic system such as anterior cingulate cortex (ACC), amygdala (AMY), and hippocampus.By analyzing relevant literature, it has been found that the regulation of acupuncture on pain emotion is mainly related to the activation of pertinent opioid receptors in the ACC, the decrease of the expression of extracellular signal-regulated kinase (ERK), and the promotion of the expression of glutamic acid (Glu) A1, metabotropic glutamate receptor-1 (mGluR1), and γ-aminobutyric acid aminobutyric acid (GABA) B2 protein in the AMY. The regulation of acupuncture on pain cognition is mainly related to the elevation of the expression of protein kinase A (PKA) and phospho-p38 mitogen-activated protein kinase (phospho-p38 MAPK) and the inhibition of cyclic adenosine monophosphate (cAMP)/PKA/cAMP response element-binding protein (CREB) signaling pathway in the ACC.

Keywords: Acupuncture Therapy; Acupuncture Analgesia; Pain; Limbic System; Gyrus Cinguli; Amygdala; Hippocampus;Receptors, Opioid

In 2016, the International Association for the Study of Pain revised the definition of pain as “pain is a distressing experience associated with actual or potential tissue damage with sensory, emotional,cognitive and social components”[1]. This definition indicates that pain, as a complex physiological and psychological activity, includes at least the following three dimensions: pain sensation, pain emotion, and pain cognition[2-3]. The three dimensions interact with each other, which is one of the main reasons why chronic pain is difficult to cure in clinical settings[2,4].How to achieve multi-dimensional regulation involving pain sensation, pain emotion, and pain cognition has become a focus of research.

Acupuncture and moxibustion show clear efficacy in dealing with pain. The latest research has suggested that acupuncture can not only relieve the pain sensation of patients, but also significantly improve and regulate pain emotion and pain cognition induced by pain[5-7]. The limbic system of the brain is closely related to emotional responses, learning, and memory. Studies have found that this system is an important area involved in acupuncture analgesia. Such brain regions of the limbic system as anterior cingulate cortex (ACC),amygdala (AMY), and hippocampus play an important role in regulating pain sensation, pain cognition, and pain emotion[8]. However, the mechanism of these brain regions in the multi-dimensional regulation of acupuncture on pain has not been fully elucidated.Therefore, starting from the limbic system that is closely related to pain-emotion-cognition, this paper summarizes the mechanism of the related brain regions of the limbic system in the intervention of acupuncture in pain emotion and pain cognition, in order to provide a reference for improving the efficacy of acupuncture in treating pain diseases and also for follow-up studies.

1 Influence of Acupuncture on Pain

1.1 Influence of acupuncture on pain emotion

Negative emotional manifestations associated with pain, abbreviated as pain emotion, refer to the emotional states induced by pain, including short-term or long-term fear, tension, anxiety, and depression[3].Pain sensation and pain emotion are closely related,and the two influence each other. With the development of medical science, the influence of psychological factors on human health and disease has been paid more and more attention, and the studies on pain emotion are being deepened. Studies have suggested that acupuncture can improve pain-induced negative emotional manifestations[5]. LI Q,et al[6]gave electroacupuncture (EA) stimulation to rats with neuropathic pain and found that EA significantly relieved the depression and anxiety induced by neuropathic pain. Numerous animal experiments have confirmed that EA stimulation can alleviate the pain emotion induced by complete Freund’s adjuvant in rats[9-10].

1.2 Influence of acupuncture on pain cognition

Pain cognition mainly refers to the information exchange and integration between cortical nuclei caused by current pain experience, including memory,attention, and anticipation, based on past pain experience and pain understanding[3]. Pain memory refers to the phenomenon that after the initial cause of pain (such as inflammatory reaction, trauma, etc.) is eliminated, the nociception caused by pain still exists,and occurring of similar situations may lead to such reactions as aversion and avoidance[4]. The existence of pain memory makes many patients with chronic pain still feel pain after the primary pain of the disease is eliminated, which is an important internal cause of chronic pain in clinical settings[7]. SUN J,et al[7]have found that compared with non-steroidal anti-inflammatory drugs, EA has significant advantages in dealing with chronic pain, and it can intervene in both pain sensation and pain memory of patients. In addition, a large number of clinical trials have confirmed that acupuncture has significant effects on cognitive dysfunction caused by stroke or brain injury[11-12]. These findings suggest that acupuncture can positively intervene in the pain cognition of patients.

2 Role of Limbic System in Acupuncture Analgesia

The limbic system is involved in brain activities,including memory, sensation, and emotion. Such related brain regions as ACC, AMY, and hippocampus in the limbic system play an important role in multidimensional regulation of acupuncture analgesia. The AMY is related to acupuncture intervention in pain emotion, the hippocampus is closely related to acupuncture intervention in pain cognition, and the ACC plays an important role in both aspects.

2.1 Pain emotion

Patients with pain often suffer from abnormal sensations and emotions. Long-term chronic pain often leads to anxiety and depression. The latest studies have found that ACC and AMY can accept the transmission of pain signals and ultimately induce pain emotion[13].

2.1.1 ACC and pain emotion

As the advanced center of pain emotion, the ACC participates in the processing of such information induced by pain as anxiety and depression and plays a crucial role in the interaction between pain sensation and pain emotion[14]. SELLMEIJER J,et al[15]have found that such pain emotions induced by pain as anxiety and depression are closely related to the overexcitation of ACC in 24a/24b area. FU T T,et al[16]have observed the influence of pain emotion on pain sensation and found that ACC is the basis of pain emotion; blocking the generation of pain emotion can relieve pain sensation.GAO Y J,et al[17]have confirmed that the ACC is related to the generation of pain emotion. FOLTZ E L,et al[18]have found that resecting the ACC and its surrounding cortical tissue in patients with pain can significantly relieve the emotional reactions of patients including anxiety and depression.

The improvement effect of acupuncture in pain emotion is closely related to its regulation of the activity of related opioid receptors in the ACC. Opioid neurotransmitters can regulate brain regions related to emotional processing. When the body produces negative emotions, opioid neurotransmitters become inactive[19]. Some studies have found that EA plays an analgesic role by promoting the release of opioids from the central nervous system, while the ACC endogenous opioid signal can relieve pain emotion, suggesting that EA may relieve pain emotion by promoting the release of opioid peptides from the central nervous system[20-21].Some studies have found that damaging the rostral ACC(rACC) can block the generation of pain emotion in rats.The rACC mainly contains μ-, δ-, and κ-opioid receptors[22-23]. Animal experiments have found that EA stimulation can reduce the phosphorylation expression of NR1, NR2A, and NR2B in the N-methyl-D-aspartate acid (NMDA) by activating δ-, μ-, and κ-opioid receptors,and thus reverse the enhancement of neuronal electrical activity and conditioned place avoidance in rats to relieve pain emotion[24-26]. Other studies have found that the activation of extracellular signalregulated kinase (ERK) in the ACC plays an important role in the generation and maintenance of pain emotion.EA can reduce the anxiety-like and depression-like behaviors of rats with neuropathic pain by lowering the expression of ERK in the ACC[27].

2.1.2 AMY and pain emotion

The AMY comprises a group of nuclei and is called“emotional brain”. It is a key structure in the brain to regulate physiological reactions such as anxiety- and fear-related behaviors, autonomous activities, and hormone levels[8]. DUANMU C L,et al[9]have found that the AMY plays an important role in the processing of pain sensation and emotion. The AMY is a core region involved in the expression of negative emotions in the brain, and damage to the central AMY can prevent the production of conditioned aversion[28-29]. SENKOWSKI D,et al[30]have conducted a study on healthy people to examine the influence of negative emotions on pain sensation. The results of this study showed that the cases felt more pain when receiving electrical stimulation in a negative environment, and this enhancement was related to the activation of the ACC and AMY. GIESECKE T,et al[31]have studied the brain imaging of patients with chronic muscle fiber pain accompanied by depression and found that the depression severity of patients is not related to tenderness sensitivity or the activity of somatosensory cortex, but is related to the activity of emotion-related brain regions (such as the AMY and insula). CROWN E D,et al[32]have found that impairing the AMY in rats can improve the negative emotional state induced by pain.

The AMY plays an important role in the processing of pain sensation and pain emotion. Both glutamic acid(Glu) and γ-aminobutyric acid (GABA) in the AMY are involved in regulating pain sensation and pain emotion[33]. Acupuncture can improve pain emotion by regulating Glu and GABA in the AMY. Glu is an excitatory neurotransmitter, while GABA is an inhibitory neurotransmitter[34]. Glu can control the generation of pain sensations and regulate the behaviors induced by pain, including anxiety and depression[35]. YAN Y X,et al[36]have found that EA can not only reduce pain sensation in rats with chronic neuralgia, but also relieve pain emotion by elevating the expression of GluA1 protein in the AMY. FENG X M,et al[10]have found that acupuncture can significantly improve pain sensation and pain emotion in rats with chronic pain, which may be related to elevating the expression of GABA receptor subtypes in the AMY, including GABAaR and GABAcR.DUANMU C L,et al[9]have found that repeated EA can significantly improve pain sensation and pain emotion in rats with chronic pain, which may be related to elevating the expression of mGluR1 and GABAB2 proteins in the AMY.

2.2 Pain cognition

The influence of pain on individuals can be manifested in cognition. Patients’ attention, anticipation,and memory of their current pain are called pain cognition[3]. Some studies have found that patients with chronic pain often have weakened cognition. The hippocampus and ACC play an important role in the cognitive regulation of pain sensation and are the common brain regions in the processing of pain,learning, and memory[37].

2.2.1 Hippocampus and pain cognition

Located below the cerebral cortex, the hippocampus is a part of the limbic system and plays a key role in learning and memory. Research has suggested that functional changes and structural reorganization often occur in the hippocampus of patients with pain[38].Studies have shown that the hippocampus not only receives the afferent pain sensation, but also plays an important role in the modulation of pain sensation, and is closely related to the cognitive impairment caused by pain[39-40]. The hippocampus is not only a higher center for pain response and its related emotional activities,but also an important central nucleus for inhibiting pain response and emotional activities[41].

BINGEL U,et al[42]have found that the hemodynamic changes in the hippocampus and the activation of the hippocampus during pain stimulation indicate that pain signals can be uploaded to the hippocampus, and the hippocampus participates in pain perception. ZHANG C C,et al[41]have found that electrical stimulation to the dorsal hippocampus in rats can increase their pain threshold and produce analgesic effects, and also found that the hippocampus is related to the activities of pain and emotion. The hippocampus plays an important role in the cumulative effect of acupuncture analgesia,which may be closely related to its involvement in the regulation of neural memory. WANG J Y,et al[43]have found that repeated EA at Zusanli (ST36) and Yanglingquan (GB34) has cumulative analgesic effects,which may be related to the elevation of protein kinase A expression in the hippocampus and the neural memory of rats. Other studies have found that the cumulative effects of EA analgesia is also related to the elevation of phospho-p38 mitogen-activated protein kinase (phospho-p38 MAPK) in the hippocampus[44-45].

2.2.2 ACC and pain cognition

In addition to mediating the regulation of pain emotion, ACC is closely related to the regulation of pain memory. The ACC may be a key brain region where pain emotion and pain cognition interact, and may participate in the upward pain cognition loop.

Studies have found that EA can effectively weaken pain memory, and this effect is related to the inhibition of the activity of the ACC region. SHAO X M,et al[46]have found that the cyclic adenosine monophosphate(cAMP)/PKA/cAMP response element-binding protein(CREB) signaling pathway in the ACC is closely related to pain memory. KIM M H,et al[47]have found that cAMP is involved in the process of learning and memory upstream protein of pain memory pathway. PKA is closely related to cAMP, and the increase of cAMP in cells will accelerate the phosphorylation of PKA basement[48]. WU W,et al[49]have found that cAMP/PKA signaling pathway plays an important role in memory consolidation. CREB, as a downstream transcription factor, is closely related to pain and also a core protein for memory storage[50-51]. SUN J,et al[52]have found that the activation of CREB in the ACC brain region is closely related to the awakening of pain memory. EA can weaken pain memory by lowering CREB in the ACC. SUN J,et al[7]found that after EA intervention, positive cAMP cells in the ACC region of rats with pain memory model were significantly reduced, the PKA expression was significantly inhibited, and the CREB phosphorylation level was significantly reduced, indicating that EA has a direct intervention in pain memory mainly through inhibiting the signaling pathway of cAMP/PKA/CREB.

3 Discussion

Pain is a complex physiological and psychological activity involving at least three dimensions, including pain sensation, pain emotion, and pain cognition. The three dimensions influence each other. Pain can activate the cerebral cortex related to sensation, as well as the large brain regions and some subcortical structures related to cognition and emotion[53-54].Acupuncture can regulate and improve the three dimensions of pain to a certain extent, which is closely related to the ACC, AMY, and hippocampus in the limbic system.

The current studies on pain mainly focus on pain sensation, while those on pain emotion and pain cognition are still shallow and lack comprehensive and multi-dimensional pain regulation methods.Acupuncture has a definite effect on emotional and cognitive disorders and has been widely used in clinical practice[55-57]. However, the current studies on acupuncture intervention and regulation of pain emotion and pain cognition mostly focus on animal experimentation, lacking high-quality clinical research support, and further multicenter and large-scale clinical studies are needed to confirm its efficacy. In addition,the complex brain mechanism of pain emotion and pain cognition (such as the interaction and mutual influence of the ACC, AMY, and hippocampus) and the expression regulation of specific molecules (neurotransmitters and receptor proteins) have not been fully clarified. In the future, we can start from the neural functional brain regions, circuits, and molecular mechanisms found in recent years that are closely related to emotion and cognition and conduct studies on multi-dimensional regulation mechanisms of acupuncture for pain sensation, pain emotion, and pain cognition, in order to and long-term changes in synaptic plasticity. It is the provide a basis for improving the efficacy of acupuncture in treating pain diseases.

Conflict of Interest

The authors declare that there is no potential conflict of interest in this article.

Acknowledgments

This work was supported by 2021 Scientific Planning Project of Gansu Province (2021 年甘肅省科技計(jì)劃項(xiàng)目;No. 21JR1RA266); Project of National Natural Science Foundation of China (國(guó)家自然科學(xué)基金項(xiàng)目, No.81460744).

Received: 13 July 2021/Accepted: 18 October 2021