Research Background:

The electroacupuncture analgesic effect has been widely recognized worldwide, but its exact target of the central nervous system and cell-specific analgesic mechanisms are still not fully understood. [1-3]. Studies have confirmed that electroacupuncture can induce specific expression of c-fos in the periaqueductal gray (PAG) of the midbrain aqueduct [4], and the ventrolateral periaqueductal gray (vlPAG) is interposed. An important component of the neural pathway that guides pain regulation [5].

The endogenous analgesic substances opioid peptides and cannabinoids activate the descending pathway by indirectly inhibiting the inhibitory effect of local GABAergic interneurons, thus depressing the output neurons to the pain signaling of the spinal cord [6]. The endocannabinoid system is an important neuromodulatory system in the central nervous system that controls pain conduction and acupuncture analgesia, and its mediated anti-nociceptive effect plays an important role in the activation of the descending inhibitory analgesia pathway [7-8 ].

GABAergic neurons and glutamatergic neurons in vlPAG play an important and complex role in nociceptive information processing. Microinjection of glutamate agonists or GABA antagonists in vlPAG can produce significant antinociceptive effects [9,10]. Cannabinoid receptor 1 (CB1) is expressed in GABAergic neurons and glutamatergic neurons in PAG, and activation of CB1 receptor may regulate GABAergic and glutamatergic neurons. Pass [11-12]. Previous studies have shown that CB1 receptors are involved in electroacupuncture analgesia [13]. So are GABAergic neurons and glutamatergic neurons in vlPAG involved in CB1 receptor-mediated electroacupuncture analgesia?

On May 17, 2019, Li Wei team of the Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, published online " Fontiers in Neuroscience" entitled "Inhibition of GABAergic Neurons and Excitation of Glutamatergic Neurons in the Ventrolateral Periaqueductal Gray Participate in Electroacupuncture Analgesia Mediated by Cannabinoid Receptor" article. The study found that electroacupuncture activates GABAergic neurons in vIPAG and inhibits glutamatergic neurons through CB1 receptors. The CB1 receptor on GABAergic neurons in vIPAG is an important target for electroacupuncture analgesia. point. This study provides new experimental evidence for the mechanism by which electroacupuncture can produce analgesic effects through bidirectional regulation of GABAergic neurons and glutamatergic neurons in vIPAG.

Electroacupuncture can effectively reduce the pain sensitivity of CCI and KOA mice

First, the team used a similar method to the rat sciatic nerve chronic injury (CCI) [14] to produce neuropathy to prepare the CCI model ; the left knee joint injection of monosodium iodate (MIA) was used to induce the knee bone. Arthritis (KOA) model . Treatment of CCI and KOA mice by electroacupuncture revealed that electroacupuncture significantly increased its mechanical pain threshold and thermal pain threshold (Fig. 1A-D). And in the conditional position preference experiment, the mice stayed in the bright box for a significant increase after conditional pairing with electroacupuncture treatment (Fig. 1E-H).

Figure 1. Electroacupuncture can effectively reduce the pain sensitivity of CCI and KOA mice

Inhibition of analgesic effects of GABAergic neurons in vlPAG

In order to verify whether the inhibition of GABAergic neurons in vlPAG can exert an analgesic effect , the research team applied the chemical genetics strategy to rAAV-mDlx-CRE-WPRE-pA virus and rAAV-hSyn-DIO-hM3D(Gi)-mCherry The -WPRE-pA virus mixture was injected to the right of the CCI and KOA mouse vlPAG in order to specifically inhibit the activity of GABAergic neurons (Fig. 2A). This virus mixture was also injected into the right vlPAG region of GAD67-GFP mice to verify viral transfection efficiency (Fig. 2B, C). Approximately 80.5% of the labeled neurons in vlPAG colocalize with GAD67-GFP positive neurons (Fig. 2D).

Figure 2. Virus mixture labeling rate

Subsequently, chemical genetic suppression of CBI and KOA mouse GABAergic neurons can effectively mimic the effects of electroacupuncture, including analgesic effects (Fig. 3A–H).

Figure 3. Chemical genetic inhibition of GABAergic neurons in VlPAG can mimic the effects of EA

Activation of GABAergic neurons in vlPAG can only partially attenuate the analgesic effect of electroacupuncture

Next, in order to verify whether the activation of GABAergic neurons can reverse the analgesic effect of electroacupuncture. The team injected the rAAV-mDlx-CRE-WPRE-pA virus and the rAAV-hSyn-DIO-hM3D(Gq)-mCherry-WPRE-pA virus mixture into CCI and KOA mouse vlPAG for the purpose of activating GABAergic neurons.

It was unexpectedly discovered that activation of GABAergic neurons in vlPAG only partially reduced the mechanical pain threshold and thermal pain threshold in the electroacupuncture group (Fig. 4A-D), and only partially reduced the mice in the conditional position preference experiment. Stay in the clear box (Figure 4E-H).

Figure 4. Chemical activation of GABAergic neurons in vlPAG only partially attenuates the effects of EA

Activation of GABAergic neurons and inhibition of glutamatergic neurons in vlPAG can effectively antagonize the analgesic effect of electroacupuncture

Activation of GABAergic neurons alone can only partially attenuate the analgesic effect of electroacupuncture, in order to verify that GABAergic neurons and glutamatergic neurons are involved in the analgesic effect of electroacupuncture. The team used rAAV-CaMKIIa-HA-KORD-IRES-mCitrine-WPRE-pA virus to selectively inhibit the activity of glutamatergic neurons in vlPAG, based on the activation of GABAergic neurons in vlPAG. It was found that activation of GABAergic neurons in vlPAG and inhibition of glutamatergic neurons in vlPAG can significantly reduce the mechanical contraction threshold and thermal pain threshold of mice (Fig. 5A-D), as well as in conditional position preference experiments. The time of the box stay (Fig. 5E-H).

Figure 5. The chemical activation of GABAergic neurons in vlPAG combined with the chemical inhibition of glutamatergic neurons in VlPAG can effectively attenuate the effects of electroacupuncture

The CB1 receptor on GABAergic neurons is involved in the role of electroacupuncture in hypersensitivity to pain

Next, in order to verify whether the CB1 receptor expressed on the axons of GABAergic and glutamatergic neurons in vlPAG is involved in the analgesic effect of electroacupuncture. The researchers injected rAAV-mDlx-CRE-WPRE-pA virus into the right vlPAG of mCnr1flox/flox mice constructed in Saiye Biotechnology , specifically knocking out the CB1 receptor on GABAergic neurons in vlPAG; at mCnr1flox/flox The rAAV-CaMKII-CRE-WPRE-pA virus was injected into the right vlPAG of mice, specifically knocking out the CB1 receptor on glutamatergic neurons in vlPAG (Fig. 6A, C).

Figure 6. Specific knockdown of CB1 receptors on GABAergic neurons located in vlPAG

It was found that specific knockout of CB1 receptors on GABAergic neurons can eliminate the analgesic effect of electroacupuncture, significantly reducing the mechanical pain threshold and thermal pain threshold (Fig. 7A-D) and in the conditional position preference experiment. The length of stay of the box (Figure 7E-H). Specific knockout of the CB1 receptor on glutamatergic neurons in vlPAG only slightly attenuated the analgesic effect of electroacupuncture. The results indicate that the CB1 receptor located on GABAergic neurons in vlPAG is the basis for electroacupuncture to exert analgesic effect.

Figure 7. Specific knockout of GABAergic neurons. CB1 receptors eliminate the effects of electroacupuncture on pain response.

In conclusion, this study demonstrates a novel mechanism of GABAergic neurons and glutamatergic neurons in vlPAG in the electroacupuncture analgesic effect , that is, electroacupuncture can simultaneously inhibit GABAergic neurons in vlPAG and activate vlPAG in the valley through CB1 receptor. Alanine neurons exert an analgesic effect. Specific knockout of CB1 receptors on GABAergic neurons can completely eliminate the analgesic effect of electroacupuncture, and only activation of GABAergic neurons in vlPAG combined with inhibition of glutamatergic neurons in vlPAG can completely reverse electroacupuncture Analgesic effect. Electroacupuncture can simultaneously exert different regulatory functions on the GABAergic system and the glutamatergic system through the CB1 receptor. This study may provide a new idea for the development of clinical pain treatment and analgesic drugs.

About the Author:

Li Wei, born in 1973, is a doctoral, professor, postgraduate tutor, and doctoral tutor. Deputy Secretary General of the Hubei Society of Neuroscience and Executive Director of the Wuhan Acupuncture Society. Editorial board of evidence-based complementary and alternative medicine.

He graduated from Hubei College of Traditional Chinese Medicine in June 1995 and obtained a bachelor's degree in acupuncture. In June 1998, he graduated from Hubei College of Traditional Chinese Medicine and obtained a master's degree in acupuncture. In June 2001, he obtained a combination of Chinese and Western medicine in the Department of Neurobiology of Tongji Medical University. A Ph.D. in Basic Professional Medicine, as a major participant in the National Natural Science Foundation of the People's Republic of China (No.39970889), and a series of exercises on the peripheral mechanism of electroacupuncture treatment of inflammatory pain. Research, mastered the frontier knowledge of meridian essence and acupuncture analgesia principle research, and accumulated rich technical experience; in July 2001, he was a lecturer at the Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology; July 2003 Associate Professor, Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology; March-September 2007, in the Department of Anatomy, University of New South Wales, Australia, studied for one and a half years, studied the mechanism of peripheral complement involvement in neuropathic pain, and mastered various The preparation method and research ideas of inflammatory pain and neuropathic pain model have laid a solid foundation for the study of the principle of acupuncture analgesia Basis; in September 2007, returning home, Associate Professor, Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology in; November 2009 so far in Biology, Tongji Medical College, Huazhong University of Science professor nerve. Hosted or participated in 12 national and provincial scientific research projects such as the National Natural Science Foundation, and guided the graduate students to obtain 3 outstanding master's thesis awards from Hubei Province. He has published more than 30 papers in important academic journals at home and abroad. Obtained a utility model patent.

Research direction: Cellular and molecular neurobiology of pain, mechanism of acupuncture on pain adjustment

Original search:

Inhibition of GABAergic Neurons anExcitation of Glutamatergic Neurons in the Ventrolateral Periaqueductal Gray Participate in Electroacupuncture Analgesia Mediated by Cannabinoid Receptor .

Doi: 10.3389/fnins.2019.00484

references:

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This article was written by Professor Li Wei and edited by Saiye Bio.

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