Qiufu Ma et al. / Nature, 2021

The anti-inflammatory effect of electroacupuncture stimulation is realized through sensitive neurons expressing the PROKR2-Cre protein. From these neurons, a reflex chain begins, continuing in the nuclei of the vagus nerve and finally releasing catecholamines from the adrenal glands, which have an anti-inflammatory effect. How reported In the magazine Nature, these results provide a more detailed explanation of the neuroanatomical foundations of acupuncture and will be useful in the development of new therapies.

The main idea of ​​acupuncture is that stimulating certain areas of the body – acupuncture points – can affect processes in other, distant, parts. Traditionally, it is assumed that such an effect is realized through hypothetical meridian channels, the existence of which has so far been confirmed by anyone. failed… However, attempts are made to explain these effects using somatosensory autonomous reflexes. By opinion a number of scientists, stimulation of receptors of sensitive neurons in certain parts of the body can through reflex circuits drive to the activation of the autonomic nervous system. However, the neuroanatomical basis of such reflexes remained unexplored.

Qiufu Ma and colleagues from Harvard University and several Chinese institutes tested in mice through which pathways electroacupuncture stimulation at the acupuncture point of the hind limb Tszu-san-li (ST36) affects the vagus-adrenal axis and thus, reduces the activity of inflammation. In addition, the Tien Shu abdominal acupuncture point (ST25) was examined, in which electroacupuncture stimulation activated spinal sympathetic reflexes, but no anti-inflammatory activity was noted. Scientists hypothesized that somato-vagal-adrenal reflexes (the vagus-adrenal axis) are controlled by sensory pathways starting from joints, bones or skeletal muscles, and the main stimulation effect is realized by sensory neurons with the PROKR2-Cre receptor, which innervate deep tissues of the extremities, but not the epidermis of the skin.

Scientists have genetically modified mice to better study PROKR2-Cre neurons. Neurons were found in the spinal ganglia, and more of them were found at the level of the extremities than at the level of the thoracic segments. In addition, these neurons could not be found in the sympathetic and intestinal ganglia and adrenal glands, while in the nodular ganglia they were found in minimal numbers (p <0.001).

The scientists then studied the patterns of innervation. In the hind limb, fibers of PROKR2-Cre sensory neurons tightly innervated the periosteum, articular ligaments, and the interosseous membrane between the tibia and fibula. PROKR2-Cre neurons accounted for 38.7 percent of all neurons that led from the deep tissues of the ST36 acupuncture point. In contrast, the scientists did not find the fibers of these neurons in the peritoneum (at point ST25).

To study the functions of PROKR2-Cre neurons, a group of genetically modified mice was bred, in which the number and function of these neurons were reduced. With electroacupuncture stimulation of the ST36 point of the hind limb in mice from the control group (with functioning neurons), even a low current intensity (0.5 milliamperes) was sufficient to induce the expression of the neuron activation marker Fos in vagus efferent hindbrain neurons located in the dorsal motor nuclei of the vagus nerve. In them, upon stimulation, the expression of choline acetyltransferase was noted. In mice with blocked PROKR2-Cre neurons, such neuronal activation was not observed.

Besides, knownthat stimulation of the ST36 point triggers the release of norepinephrine, adrenaline and dopamine from adrenal chromaffin cells, which are dependent on the vagus nerve. This surge was not observed in the group of mice with reduced function of the PROKR2-Cre neurons. Since also studiedthat activation of the vagus-adrenal axis can suppress systemic inflammation caused by lipopolysaccharide through the effects of catecholamines (epinephrine and norepinephrine) in the control group of mice, stimulation of the ST36 point showed a 50 percent decrease in the induction of pro-inflammatory cytokines and a 40 percent increase in survival compared with fictitious stimulation, and in the studied group of mice, these effects were not found at all.

Previously reportedthat electroacupuncture stimulation of the abdominal ST25 point with a current of 0.5 milliamperes does not induce wandering or sympathetic reflexes and cannot suppress systemic inflammation. However, in this experiment, scientists found both weak (at 1 milliampere) and strong (at 3 milliamperes) anti-inflammatory effects, regardless of the effects of the vagus nerve. Such effects of electroacupuncture stimulation were observed in both groups of mice.

In addition, at 3 milliamperes, stimulation of the ST36 acupuncture point of the hind limb also stimulated spinal sympathetic reflexes and had an anti-inflammatory effect independently of the PROKR2-Cre neurons. Thus, these neurons play a dominant role in low-intensity stimulation in driving the anti-inflammatory axis of the vagus-adrenal gland from the ST36 acupuncture point of the hindlimb.

This conclusion was confirmed by experiments on optogenetic stimulation of PROKR2-Cre neurons. Optogenetic deep tissue stimulation at ST36 mimicked electroacupuncture stimulation with a current of 0.5 milliamperes and could induce the same anti-inflammatory effects through activation of the vagus-adrenal axis.

All these data will allow, according to the authors of the work, to optimize the methods of bioelectric stimulation in the management of various vegetative pathways for the treatment of diseases. So, if electroacupuncture can selectively activate certain neural networks, it could be used to activate local anti-inflammatory mechanisms in certain parts of the body – such as an arthritic knee or certain parts of the digestive tract in people with chronic inflammatory bowel disease – without suppressing the entire immune system and increasing risk of infection.

Although the therapeutic use of acupuncture is still controversial due to the weak evidence base, a 2016 meta-analysis showed, acupuncture relieves sleep disturbances in menopausal women. And at the Mayo Clinic acupuncture named effective for back pain.

Glory Gomenyuk

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