Hypothesis, Modern Researches and Clinical Applications of Cutaneous Regions in Traditional Chinese Medicine

Shanghai Research Institute of Acupuncture and Meridian, Shanghai 200030, China

CRITICAL REVIEW

Hypothesis, Modern Researches and Clinical Applications of Cutaneous Regions in Traditional Chinese Medicine

Fan Lei, Yin Lei-miao

Shanghai Research Institute of Acupuncture and Meridian, Shanghai 200030, China

Author: Fan Lei, doctorate candidate

As one of the most important concepts in traditional Chinese medicine, cutaneous regions have a close relationship with skin in modern medicine. According to the doctrine of traditional Chinese medicine, the cutaneous regions are the corresponding projections of twelve meridians in the superficial layer of the body and play an important role in body surface-viscera correlation. The symptoms of visceral disorders will reflect on cutaneous regions and one of the major patterns of manifestation is referred visceral pain accompanied by tenderness and hyperalgesia on the body surface. On the contrary, cutaneous regions participate in the treatment of visceral disorders. As major clinical applications of the cutaneous regions hypothesis, superficial acupuncture, subcutaneous needling, massage (tuina), moxibustion, and wrist-ankle acupuncture have achieved favorable therapeutic outcomes in clinical practice. Modern researches have gained insights into the biological background of cutaneous regions, however, further studies are needed to clarify the mechanisms.

Cutaneous Regions; Body Surface-viscera Correlation; Superficial Acupuncture; Subcutaneous Needling; Massage; Tuina; Moxibustion Therapy; Wrist-ankle Acupuncture

The hypothesis of cutaneous regions is one of the most important concepts in traditional Chinese medicine, which is an ancient medical system but has a close relationship with skin in modern medicine[1]. The cutaneous regions are subsidiary parts of the twelve meridians[2]，which was first documented inHuang Di Nei Jing(Yellow Emperor’s Classic of Internal Medicine)[3]. The distribution pattern of cutaneous regions on the body surface is based on the pathways of twelve meridians and the cutaneous regions communicate with each other between hand and foot meridians, which share the same name among the hand and foot meridians and then converge into six regions, named ‘Taiyang-Guanshu’, ‘Shaoyang-Shuchi’,‘Yangming-Haifei’, ‘Taiyin-Guanzhe’, ‘Shaoyin-Shuru’, ‘Jueyin-Haijian’, respectively[4]. As the corresponding projections of twelve meridians on surface skin, the cutaneous regions distribute more extensively than meridians and collaterals, which are not linearly distributed. In this way, the cutaneous regions-collateral-meridian-viscera constitute an organic whole maintaining body homeostasis.

Based on the same biological basis, cutaneous regions are in close relationship with the skin in the modern medicine, which is the largest organ of the body[5]. Skin has been well documented to contain multiple sensory receptors for temperature, mechanical stimuli, electric potentials, and other stimuli[6]. These skin sensory receptors produce changes in membrane potential and activate signal transduction pathways such as mitogen-activated protein kinase signal transduction pathway[7], and nitric oxide-cyclic guanosine monophosphate transduction pathway[8], thus lead to a variety of biological effects[9]. The sensory information induced by stimulation of skin transmits to the prefrontal cortex and hypothalamus, then transforms into signals regulating the diverse organs of the body via its control over the autonomic nervous system[10]and its powerful metabolic and endocrine capabilities[11]. Cutaneous resident and recruited cells express a wide range of hormones, neuropeptides, and steroid receptors through which the central nervous system (CNS) can communicate with the skin[10]. As for the well-known hypothalamus-pituitary-adrenal axis, the skin cells express corticotropin-releasing hormone, urocortin, and pro-opiomelanocortin, with its products adrenocorticotropic hormone, αmelanocyte-stimulating hormone, and β-endorphin, which altogether regulate stress reaction[12]. The neuropeptide Y expressed by skin cells is also responsible for regulation of the hypothalamicpituitary-thyroid axis[13]. Therefore skin is a complex organ able to maintain internal homeostasis through multidirectional communications between the endocrine, immune, and CNS which share agents of neuropeptides, cytokines, hormones, and other effector molecules, known as the neuro-immunocutaneous-endocrine system[14]. The cutaneous regions-collateral-meridian-viscera network may have identical effect as the neuro-immuno-cutaneousendocrine system in maintaining the homeostasis. We propose that the cutaneous regions may have a similar function with the skin and form a signal-gathering network, which plays a key role in whole-body homeostasis in response to the changing environment. An investigation into this area may help us better interpret the underlying mechanisms of therapeutic effects of traditional Chinese medicine.

The study aims to summarize the relationship between cutaneous regions and visceral organs, collect evidences for the biological basis of the cutaneous regions by investigating a variety of sensory receptors, and clarify the possible role of cutaneous regions in clinical applications of traditional Chinese medicine therapies.

1 Cutaneous Regions Reflect the Body Surfaceviscera Correlation

1.1 From inside to outside: symptoms of visceral disorders will reflect on cutaneous regions

According to the doctrine of traditional Chinese medicine, the cutaneous regions are the outermost layer of the body. It is not only the body's first barrier against the exogenous pathogenic factors, but also the surface reaction areas of visceral organs. As a result, visceral disorders are reflected on cutaneous regions, manifested as referred visceral pain accompanied by tenderness and hyperalgesia on the body surface[15]. Previous researches summarized referred visceral pain, such as the left shoulder pain occurred in myocardial ischemia, and interscapular pain occurred in stomach and pancreas diseases[16]. Pain associated with angina pectoris, or myocardial infarction is referred to the left chest, left shoulder, and left arm, which cover the cutaneous regions of Yangming, Taiyin, Jueyin, and Shaoyin Meridians. Further research is needed to clarify the specificity of the cutaneous regions and referred pain. Apart from referred pain, there are tenderness and hyperalgesia observed in many visceral disorders, and manipulation or needling at these sensitive points can often relieve the pain and discomfort associated with the visceral disorders[17].

Except fore sensory changes such as referred pain and hyperalgesia, ancient practitioners had often detected the activities of organs and meridians by observing the color, touching and pressing cutaneous regions to percept special pathological responses such as papules, maculopapule, and nodules. Some of these cutaneous pathological changes have been verified by modern researches. For instance, visible changes on the body surface such as scleroderma[18]and lupus erythematosus[19]are bound up with various immune-related diseases. Furthermore, hepatitis B virus infection was reported to elicit cutaneous damages manifested as skin rash, urticarial or maculopapular, purpuric and petechial lesions[20]. It’s also found that diarrheal disorder caused by vibrio cholera infection is companied with skin lesion[21], which further proves that cutaneous regions are associated with internal organs and the changes of cutaneous regions may reflect the visceral disorders.

1.2 From outside to inside: cutaneous regions play an important role in the treatment of visceral disorders

Exogenous pathogenic factors can affect viscera function through cutaneous regions. For instance, it’ssuggested that streptococcal skin infection can elicit acute nephritis or unexplained hematuria[22]. In terms of treatment, various forms of therapeutic approaches can be implemented on cutaneous regions, such as plum-blossom needles, blood-letting puncture, direct scarring moxibustion, indirect moxibustion, wrist-ankle acupuncture, massage (tuina), and cupping. Cutaneous regions have played an important role in the treatment of visceral disorders using various traditional Chinese medicine therapies, which can rearrange the function status of vital energy (meridian-qi) and visceral organs by means of transmitting diverse stimulation through cutaneous regions. Modern clinical studies demonstrate that plum-blossom needles can acquire satisfactory therapeutic benefits in the treatment of craniofacial diseases such as juvenile myopia[23], and acute facial paralysis[24]. The face belongs to the cutaneous region of Yangming Meridian, which indicates that plum-blossom needles are effective in treating diseases located in cutaneous region of Yangming Meridian. Some study found the therapeutic benefits of combining encircling needling, bloodletting with cupping therapy for patients with localized scleroderma[25].

2 Major Clinical Applications of the Hypothesis of Cutaneous Regions

2.1 Cutaneous regions are the sites where acupuncture manipulation gets initiated

The superficial acupuncture and subcutaneous needling take effect through the cutaneous regions which are the sites where acupuncture manipulation gets initiated. The mechanical coupling between the needle and the cutaneous regions transmit a mechanical signal to various organs via mechanotransduction[26]. The mechanoreceptors and mechanosensitive ion channels of the skin detect mechanical stimuli of acupuncture and transduce these stimuli into electrical signals in sensory neurons[27]. Study also demonstrates that stimulation excitation induced by the deformation of collagen bundle appears in mechanoreceptors innervated by Aδ and C fibres[28]. Sharp edge of acupuncture needle leads to a pinprick-like sharp pain sensation in the superficial skin related to A fiber afferent activity[29-30].

Various kinds of receptors and nerve fibers are involved in the acupuncture biological process via the cutaneous regions. Pervious study demonstrates the co-localization of the transient receptor potential vanilloid subfamily member 1 (TRPV1) and neuronal nitric oxide synthase in both the subepidermal nerve fibers and in the dermal connective tissue cells by means of double immunostaining. The higher expression of TRPV1 is found in the subepidermal nerve fibers after acupuncture treatment, which may play a key role in mediating the transduction of acupuncture signals to the CNS[31]. All of the peripheral somatosensory inputs are transmitted to the spinal cord via dorsal root ganglion (DRG) sensory neurons. Acupuncture stimulation activates DRG sensory neurons by inducing signals of axonal growth-associated protein 43 and phosphorylation of Erk1/2, which suggests that acupuncture stimulation may generate physiological effects on the autonomic nervous system via the activation of somatosensory pathways[32].

Both superficial acupuncture and subcutaneous needling achieve satisfactory therapeutic benefits compared with conventional treatment or deep needling approaches. For instance, Itoh K, et al observed that there was no statistically significant difference between direct myofascial trigger points needling and superficial needling at the end of two phases of treatment of chronic low back pain[33]. Previous study also revealed that patients with idiopathic anterior knee pain benefit equally from both subcutaneous needling and electroacupuncture treatment with a long-term pain-relieving effect for at least 6 months. The treatment effects may result from central pain inhibition caused by afferent stimulation induced by subcutaneous needling[34].

2.2 Massage (tuina) therapy has significant anti-stress effects

Massage therapy could regulate nerve function by rearranging the balance of activity and inhibition of mechanoreceptors of cutaneous regions. As massage therapy relies on cutaneous regions to receive stimulation and take effect, its biomedical basis is associated with the widely distributed cutaneous mechanoreceptors that respond to mechanical pressure or distortion[35]. It is demonstrated that mechanical deformation of the skin leads to the release of ATP from keratinocytes, fibroblasts and other cells, then the mechanoreceptors are activated through purinergic receptors[36]. It is the activation of mechanoreceptors in the periphery caused by mechanical pressure and tissue distortion that induce activity in the afferent nerve fibers which transmits signals to the brain[36].

Cutaneous regions also participate in the human psychological reaction to environments as positive effects of massage on anxiety have been shown in many studies[37-38]. Previous study demonstrated that innocuous stimulation induced by light to moderate massage resulted in a decreased activity of theadrenal glands, lowered levels of adrenaline and noradrenaline, and anti-stress effects characterised by a decreased adrenergic activity, release of oxytocin, sedation and an increase of gastrointestinal hormones[39]. On the contrary, noxious stimulation such as trigger point massage therapy was shown to affect the release of either the corticotrophin causing increased adrenal activity or higher levels of the stress hormone cortisol[39].

Cutaneous regions play a key role in massage therapy for the treatment of hypertension. As cortisol and catecholamine release involved in stress reactions are positively correlated with blood pressure, and the reduction of them could contribute a great proportion to the therapeutic benefits of massage therapy in the treatment of hypertension[40]. Similar to the role of massage therapy in stress response, its significant regulatory effects on blood pressure was reported to be determined by the certain form of massage[41]. Strong massage such as trigger point therapy and sports massage are significantly associated with an increase in systolic blood pressure[41], whereas reflexologic foot massage is effective to reduce blood pressure and improve sleep of the elderly with essential hypertension[42].

2.3 Moxibustion-induced therapeutic effects are associated with cutaneous regions

Skin is abundant in thermoreceptors that respond to changes in temperature within the innocuous range[43]. Collagen deformation caused by thermal stimulation activates mechanoreceptors and thereby leads to series of biological effects[44]. The thermoreceptors responding to warmth elicited the activity of unmyelinated C-fibres with low conduction velocity, while those responding to cold excite both C-fibers and thinly myelinated Aδ fibers with faster conduction velocity[45].

Moxibustion has been frequently used to warm regions, as it’s believed to stimulate circulation and induce a smoother flow of blood and qi and dispel cold and dampness in the body according to the doctrine of traditional Chinese medicine. Heat stimulation induced by indirect suspended moxibustion activates thermoreceptors that express the TRPV1 channels and excited autonomic nerve endings ultimately leading to axon reflex-mediated vasodilatation[46]. Specifically, substance P (SP) and calcitonin gene related peptide (CGRP) are coreleased. SP modulates the prolonged vasodilator activity of CGRP via release of proteases from cutaneous mast cells and serves to increase the local production and availability of NO[47]. This may explain the mechanisms of moxibustion-induced local engorgement and cutaneous temperature improving[48].

Different from indirect suspended moxibustion, direct scarring moxibustion can elicit thermal and nociceptor activities which may involve a more complex process of taking effect. Direct scarring moxibustion places a small cone of mugwort on the skin and burns it until the skin blisters, which then scarred after healed. During this process, nociceptors that respond to damaging stimuli by sending nerve signals to the spinal cord and brain played an important role[49]. The peripheral terminal of nociceptors under the skin is where the noxious stimuli are detected and transformed into electrical energy driven towards the CNS, which leads to the perception of pain. Direct scarring moxibustion can induce heat pain perception by the responses of thermal nociceptors, mechanothermal nociceptors, polymodal nociceptors. Most nociceptors including unmyelinated, slowly conducting C fibres and myelinated, more rapidly conducting Aδ fibres have polymodal characteristics, which share the same transducers for noxious mechanical stimuli and chemical stimuli, such as acid or capsaicin[50]. During the healing process of scarring after direct scarring moxibustion, the immune non-neural components play an important role in inflammation response.

2.4 Antinociceptive effect of wrist-ankle acupuncture relies on the cutaneous regions

Wrist-ankle acupuncture as the name implies is a style of acupuncture using specific points at the wrists and ankles, and is mostly frequently used for pain relief in various disorders[51-53]. When a needle is inserted into a designated point on surface skin and manipulated in different directions under epidermis, it is assumed to cause local tissue injury and biochemical reactions, with the release of various inflammatory and immune mediators such as noradrenaline (NA), β-endorphin, SP, CGRP[54]. Compared with conventional analgesic treatment, wrist-ankle acupuncture generates more favorable results with respect to treatment outcome. Wrist-ankle acupuncture was reported to be effective for perineal pain relief after mediolateral episiotomy[55], and showed an obvious antinociceptive effect on cancer pain[53,56]and acute lumbago[52], especially with no side effects and a longer analgesic period[56].

The involvement of diffuse noxious inhibitory control which refers to an endogenous pain modulatory pathway that has often been described as‘pain inhibits pain’ has been suggested to account for part of the wrist-ankle acupuncture-induced pain relief[57]. Noxious stimulation such as penetration of the skin by wrist-ankle acupuncture activates high threshold mechanoreceptors and activity in Aδ fibres.This afferent stimulation extends from the spinothalamic tract to the nucleus of the periaqueductal grey in the midbrain, resulting in activation of the descending inhibitory control system and thereby reduction of pain perception[39].

Wrist-ankle acupuncture therapy has also been used in the treatment of immune and metabolic diseases other than pain relief. Previous research indicated that wrist-ankle acupuncture in combination with Chinese herbal medicine acquired satisfactory therapeutic outcome in treating chronic urticaria and showed obvious advantages in decreasing relapse rate and prolonging the remission time[58]. It was also reported that wrist-ankle acupuncture achieved therapeutic effects for diabetic peripheral neuritis which improved the metabolisms of blood sugar and blood lipid, lowered down blood viscosity, and restored the functions of peripheral nerve cells[59].

2.5 Other forms of traditional Chinese medicine therapies applied on cutaneous regions

Other forms of traditional Chinese medicine therapies applied on cutaneous regions include encircling needling, plum-blossom needle, guasha (scrapping) treatment and cupping etc. Similar to wrist-ankle acupuncture, encircling needling and plum-blossom needling are applied to the surface skin and were reported to be effective in the treatment of diseases such as psoriasis[60], alopecia[61], and facial paralysis[24]. Guasha employs skin scraping to cause subcutaneous microvascular blood extravasation and bruises[62]. It has been commonly used for treating breast engorgement[63], chronic neck pain[64], and was reported to achieve hepatoprotection in chronic active hepatitis B[65].

3 Discussion

Cutaneous regions can be stimulated in a variety of ways, including superficial acupuncture, subcutaneous needling, massage (tuina), moxibustion, wrist-ankle acupuncture, encircling needling, plumblossom needle, guasha treatment and cupping and so on, determining the corresponding physiologic response. There is a huge potential for using cutaneous regions to help us treat diseases. By modulating hypothalamic-pituitary-adrenal axis activity and autonomic nervous system activity, stimulation to cutaneous regions could affect neuroendocrine function, immune function, corticosteroid production (adrenal cortex), and catecholamine function (adrenal medulla). Previous studies demonstrated that stimulation to cutaneous regions by various needling approaches achieved satisfactory therapeutic outcomes in neurological diseases such as juvenile myopia[23], acute facial paralysis[24], and diabetic peripheral neuritis[59], as well as various pain such as chronic low back pain[33], idiopathic anterior knee pain[34], acute lumbago[52], perineal pain after mediolateral episiotomy[55], and cancer pain[53,56]. Except for the therapeutic benefits mentioned above, stimulation on cutaneous regions has an obvious advantage for treating skin diseases such as scleroderma[25], chronic urticaria[58], psoriasis[60]and alopecia[61]when current therapies are not as effective or as safe as the physicians or patients would like them to be or if current medical therapies have severe side effects. Moreover, due to its regulatory effects on adrenal activity and the stress hormone cortisol[39], non-invasive stimulation to cutaneous regions such as massage (tuina) has an anti-stress effect and is frequently used in treating anxiety by psychologists[37-38]. However, we should not neglect the big gap between clinical practice and evidence-based medicine. Although there have been more and more studies reporting the effectiveness of classic traditional Chinese medicine therapies applied to cutaneous regions, the study quality is inhomogenous and some of the studies are insufficient to provide conclusive evidence for clinical practice. Physicians and researchers need to recognize that better-designed strictly-conducted clinical trials are needed to establish the true efficacy of acupuncture and other approaches on cutaneous regions.

The hypothesis of the cutaneous regions not only constitutes an important supplement to the doctrine of traditional Chinese medicine, but also brings great implications and impacts on further research and clinical applications.

It is undeniable that nowadays there are some diseases that conventional Western interventions fail to achieve satisfactory therapeutic outcome despite of the rapid development of modern science. Fortunately, traditional Chinese medicine therapies based on the hypothesis of the cutaneous regions provide us with an alternative for treating those bothersome problems such as neurological diseases, various chronic pain, stress-related skin diseases, and psychological problems. Combining conventional Western medical therapies and traditional Chinese medicine therapies based on the hypothesis of the cutaneous regions may lead to a higher response rate and less side effects and thus bring physicians many implications on further clinical applications.

What is the mechanism underlying regionspecificity when treating diseases according to the hypothesis of the cutaneous regions? As examples mentioned before, pain associated with angina pectoris, or myocardial infarction is referred to the left chest, left shoulder, and left arm, which cover thecutaneous regions of Yangming, Taiyin, Jueyin, and Shaoyin Meridians. Further researches are needed to clarify the specificity of the cutaneous regions and referred pain.

The hypothesis of cutaneous regions provides us with more evidence for better understanding the meridian doctrine[66-70]. The twelve meridians are deeply linearly distributed, while cutaneous regions distribute more extensively and cover the whole body surface. However, the cutaneous regions are the sites where acupuncture manipulation gets initiated. When treating diseases by deeply inserted needles, the stimulation induced by insertion of the needle not only leads to biological effects of cutaneous regions, but also constitutes an important part of the therapeutic effects of acupoints based on the meridian doctrine. Interestingly, clinical studies sometimes provide paradoxical evidences. It was shown that both superficial acupuncture and subcutaneous needling achieved satisfactory therapeutic benefits compared with conventional treatment or deep needling approaches. It is too early to draw a conclusion based on limited evidence, and better-designed strictly-conducted clinical trials are needed to establish the biological effects of the cutaneous regions and the twelve meridian system.

Conflict of Interest

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

Acknowledgments

This work was supported by National Natural Science Foundation of China (No.81001548, No. 81173341, No. 81173332 and No. 81202753); Shanghai Rising-star Program (No. 12QA1403000); Shanghai Key Research Program of Traditional Chinese Medicine Development (No. ZYSNXDCC-ZDYJ039); The Scientific Research Funds for Young Scholar of the Health System in Shanghai (No. XYQ2013081).

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Yin Lei-miao, M.D., associate professor.

E-mail: collegeylm@shutcm.edu.cn

R245.2

: A

Date:January 8, 2014