Electroacupuncture therapy suppresses inflammation by activating neurons

Original author: Luis Ulloa "Electro-acupuncture" can activate neurons that express a specific molecular marker, and these neurons can mediate the anti-inflammatory effects of conductive acupuncture in a sepsis (sepsis) mouse model
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Neuronal networks have evolved to have the ability to regulate organ functions
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The therapy called electroacupuncture can electrically stimulate the body's acupoints and has been used to activate neuronal networks to regulate the function of specific organs and treat various diseases.
It is an important part of the emerging discipline of bioelectronic medicine.
Components [1,2]
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However, little is known about the neuronal network that mediates the effects of electroacupuncture at specific points [1,3]
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Liu Shenbin et al.
[4] published a mouse study in "Nature" and found that for the deadly disease of sepsis, the uncontrolled inflammatory response can be inhibited by electrical stimulation of a hindlimb acupoint, while the mouse A group of neurons in the body that express Prokr2 protein plays an essential role in this
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The selection of acupuncture points is based on the body's response to the stimulation of the part [1], but some acupuncture points are ambiguous because these acupoints will respond differently to different stimuli
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The Zusanli (ST36) point on the leg is located about 2 cm below the human knee and is the most commonly used point for relieving inflammation
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However, the electroacupuncture stimulation (ES) of Zusanli will have the opposite effect due to the different stimulation intensity
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The high-intensity electrical acupuncture stimulation to Zusanli can activate the sympathetic nervous system and promote the "fight or flight" response under stress; while the low-intensity stimulation to Zusanli can activate the parasympathetic nervous system and regulate the appearance of rest.
Physiology
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If the neuron network required to activate each system can be determined, a more reliable, specific, and effective treatment method can be proposed
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Stimulating Zusanli has the potential to inhibit severe inflammation caused by infections and autoimmune diseases
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A typical example is severe sepsis, in which the inflammatory response in the patient's body due to infection will gradually get out of control, until the organ is damaged, and it becomes more dangerous than the initial infection [5]
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Sepsis is the main cause of hospital death: In the United States, even with modern antibiotics for the initial infection, sepsis still accounts for 9% of all deaths [6]
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Previous studies have shown that low-intensity electro-acupuncture stimulation on Zusanli can activate the parasympathetic nervous system.
In the parasympathetic nervous system, the vagus nerve sends brain signals to the adrenal glands located at the upper pole of the adrenal pole to inhibit severe inflammation [7]
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Liu Shenbin and others injected mice with a bacterial molecule to induce an uncontrolled inflammatory response, causing the number of inflammatory factors produced to rise to dangerous levels
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The author's research shows that the activation of the vagus nerve-adrenal gland network is mediated by neurons expressing Prokr2 at this acupoint
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Selective destruction of these neurons inhibits the anti-inflammatory effect of low-intensity electro-acupuncture stimulating Zusanli, but does not affect the activation of the sympathetic nervous system of high-intensity electrical acupuncture stimulating Zusanli
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Conversely, artificial stimulation of neurons expressing Prokr2 can simulate the effect of low-intensity electric acupuncture stimulating Zusanli, and it can also activate the vagus nerve-adrenal network and control the inflammatory response
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The results of these studies have discovered for the first time a neuronal molecular marker, which may be used to design specialized stimulation methods to control independent organ functions
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It was previously discovered that the vagus nerve-adrenal network activated by low-intensity electric acupuncture stimulation on Zusanli produced anti-inflammatory effects by inducing the adrenal glands to secrete catecholamine molecules [7]
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Catecholamines can regulate many physiological processes of a healthy body and are used to treat many diseases, such as hypotension
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Dopamine and norepinephrine, the two catecholamines, can restrain the inflammatory response by inhibiting specific immune cells and the inflammatory factors secreted by them-this effect is by activating the dopaminergic type 1 receptors and β2 adrenergic receptors on the surface of these cells Realized by the receptor [7–9]
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The research results of Liu Shenbin and others revealed that electrical acupuncture stimulation of Zusanli activates the cell pathways of the vagus nerve-adrenal network
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The cell body of the sensory neuron that expresses Prokr2 is located in the structure of the lower spinal cord called the dorsal root ganglion
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These neurons transmit sensory information from the hind limbs along the spinal cord to the nucleus tractus solitarius (NTS)-the nucleus tractus solitarius is the structure in the brain that receives sensory signals from internal organs
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In the nucleus tractus solitarius, neurons expressing Prokr2 coordinate a variety of physiological functions by activating independent neuron networks, including neurons in the dorsal motor nucleus-the dorsal motor nucleus is the brain area containing the cell body of the neurons that make up the vagus nerve [ 10]
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Clarifying how the neurons that express Prokr2 are distributed can provide key information for us to understand which nerves activate the vagus nerve-adrenal network (Figure 1)
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The location of Zusanli acupoint is exactly where the sciatic nerve is divided into sural nerve, tibial nerve and common peroneal nerve and extends to the calf.
It was previously unknown which nerves are most effective for electroacupuncture stimulation[7,11]
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Neurons expressing Prokr2 are located in the deep tissues under Zusanli, suggesting that the anti-inflammatory effect of low-intensity electric acupuncture stimulation on Zusanli depends on the deep branch of the common peroneal nerve rather than the superficial cutaneous branch of the sural nerve
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In fact, the author also confirmed that cutting the common peroneal nerve will hinder the anti-inflammatory effect of stimulating Zusanli, while cutting the tibial nerve or sural nerve has no such effect
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Figure 1 | Neuron targets of electroacupuncture
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Electric acupuncture therapy can electrically stimulate acupuncture points (specific parts of the body)
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For example, low-intensity stimulation of the Zusanli (ST36) point of the leg can reduce inflammation by activating the vagus nerve-the vagus nerve can transmit brain signals to the adrenal glands (located in the kidneys, as shown in the picture), and promote the release of anti-inflammatory catecholamine molecules , Such as dopamine and norepinephrine
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Sepsis is a potentially fatal disease that manifests as an uncontrolled inflammatory response after infection
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Liu Shenbin and others[4] used a sepsis mouse model to identify a group of sensory neurons expressing Prokr2 protein.
This group of neurons is necessary for low-intensity stimulation of Zusanli to produce anti-inflammatory effects, but not high-intensity stimulation (Figure Not shown in)
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The cell bodies of these neurons are located in the lower spinal cord, and the neurites (red lines) extend down to the hind limbs and up to the nucleus tractus solitarius (NTS) of the brain, which can affect the activity of the vagus nerve
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By analogy, Prokr2-expressing neurons in other parts of the body may also be related to acupuncture points that activate the vagus nerve-adrenal network
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The author did not find neurons expressing Prokr2 in the peritoneum that wraps the abdominal organs, and confirmed that stimulation of acupoints such as the Tianshu acupoint (ST25) in the abdomen does not cause an adrenal response [12]
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In contrast, there are a large number of neurons expressing Prokr2 in the upper segment of the spinal cord where nerves are distributed in the upper limbs, suggesting that stimulation of the Li10 acupoint at the elbow may cause the secretion of catecholamines, and this has also been confirmed by the author
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The above research has very important clinical significance, because electroacupuncture can stimulate multiple acupoints at the same time
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Learn more about how the neurons that express Prokr2 are distributed, or can tell us which acupoints costimulate to improve the therapeutic effect
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In the future, more research is needed to determine whether stimulation of Prokr2-expressing neurons at different acupoints can cause the same response or have different effects on the vagus nerve and its physiological functions
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The vagus nerve is the longest parasympathetic nerve in the body, and its nerves are distributed in multiple organs
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Stimulating the vagus nerve can produce various effects, including two anti-inflammatory mechanisms
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The first mechanism is that the vagus nerve induces the adrenal glands to release catecholamines (mainly dopamine and norepinephrine) into the blood
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The second mechanism is that the vagus nerve induces the spleen to secrete norepinephrine, which activates immune cells called lymphocytes to produce acetylcholine molecules, which inhibit another type of immune cell-splenic macrophages [13-15]
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In the future, further research is needed to confirm whether different acupoints can induce these two mechanisms in different ways
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Being able to induce target effects by activating specific neuron networks while avoiding side effects is undoubtedly a great clinical advantage
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Because drug molecules diffuse throughout the body, traditional drug therapies have non-specific side effects
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In contrast, catecholamines have a shorter half-life, only 1-4 minutes, and can work more accurately, such as promoting cardiac contraction or relaxing the airways that transport air in and out of the lungs.

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Therefore, stimulating specific neuronal networks may allow independent networks to produce catecholamines, and induce local effects in specific organs, avoiding non-specific side effects
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If electric acupuncture can selectively activate specific neuron networks, it is possible to design a locally acting electric acupuncture stimulation therapy, just like a pacemaker (an electronic device implanted in the chest cavity that can control the heartbeat)
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In this way, we are expected to stimulate local anti-inflammatory mechanisms in specific parts of the body, such as knee osteoarthritis in patients with chronic inflammatory bowel disease or specific segments of the digestive tract, through electrical acupuncture stimulation, without suppressing the body’s immune system.
It also does not increase the risk of infection or cause side effects on other parts of the body
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14.
Wang, H.
et al.
Nature421, 384–388 (2003).
15.
Huston, JM et al.
J.
Exp.
Med.
203, 1623–1628 (2006).
The original text is Electroacupuncture activates neurons to switch off inflammation The title was published in the News and Views section of Nature on October 13, 2021.
© naturedoi: 10.
1038/d41586-021-02714-0 The Queen’s University Joint Institute of Biomedicine is looking for jobs! Copyright notice: This article is translated by Springer Nature Shanghai Office
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