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      Purinergic signaling as a basis of acupuncture-induced analgesia

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          Abstract

          This review summarizes experimental evidence indicating that purinergic mechanisms are causally involved in acupuncture (AP)-induced analgesia. Electroacupuncture (EAP) and manual AP release at pain-relevant acupoints ATP which may activate purinergic P2X receptors (Rs) especially of the P2X3 type situated at local sensory nerve endings (peripheral terminals of dorsal root ganglion [DRG] neurons); the central processes of these neurons are thought to inhibit via collaterals of ascending dorsal horn spinal cord neurons, pain-relevant pathways projecting to higher centers of the brain. In addition, during AP/EAP non-neuronal P2X4 and/or P2X7Rs localized at microglial cells of the CNS become activated at the spinal or supraspinal levels. In consequence, these microglia secrete bioactive compounds such as growth factors, cytokines, chemokines, reactive oxygen, and nitrogen species, which modulate the ascending neuronal pathways conducting painful stimuli. Alternatively, ATP released at acupoints by AP/EAP may be enzymatically degraded to adenosine, stimulating in loco presynaptic A1Rs exerting an inhibitory influence on the primary afferent fibers (the above mentioned pain-sensing peripheral terminals of DRG neurons) which thereby fail to conduct action potentials to the spinal cord dorsal horn. The net effect of the stimulation of P2X3, P2X4, P2X7, and A1Rs by the AP/EAP-induced release of ATP/adenosine at certain acupoints will be analgesia.

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          Most cited references51

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          Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade.

          The involvement of extracellular nucleotides and adenosine in an array of cell-specific responses has long been known and appreciated, but the integrative view of purinergic signalling as a multistep coordinated cascade has emerged recently. Current models of nucleotide turnover include: (i) transient release of nanomolar concentrations of ATP and ADP; (ii) triggering of signalling events via a series of ligand-gated (P2X) and metabotropic (P2Y) receptors; (iii) nucleotide breakdown by membrane-bound and soluble nucleotidases, including the enzymes of ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) family, ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP) family, ecto-5'-nucleotidase/CD73, and alkaline phosphatases; (iv) interaction of the resulting adenosine with own nucleoside-selective receptors; and finally, (v) extracellular adenosine inactivation via adenosine deaminase and purine nucleoside phosphorylase reactions and/or nucleoside uptake by the cells. In contrast to traditional paradigms that focus on purine-inactivating mechanisms, it has now become clear that "classical" intracellular ATP-regenerating enzymes, adenylate kinase, nucleoside diphosphate (NDP) kinase and ATP synthase can also be co-expressed on the cell surface. Furthermore, data on the ability of various cells to retain micromolar ATP levels in their pericellular space, as well as to release other related compounds (adenosine, UTP, dinucleotide polyphosphates and nucleotide sugars) gain another important insight into our understanding of mechanisms regulating a signalling cascade. This review summarizes recent advances in this rapidly evolving field, with particular emphasis on the nucleotide-releasing and purine-converting pathways in the vasculature.
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            Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture.

            Acupuncture is an invasive procedure commonly used to relieve pain. Acupuncture is practiced worldwide, despite difficulties in reconciling its principles with evidence-based medicine. We found that adenosine, a neuromodulator with anti-nociceptive properties, was released during acupuncture in mice and that its anti-nociceptive actions required adenosine A1 receptor expression. Direct injection of an adenosine A1 receptor agonist replicated the analgesic effect of acupuncture. Inhibition of enzymes involved in adenosine degradation potentiated the acupuncture-elicited increase in adenosine, as well as its anti-nociceptive effect. These observations indicate that adenosine mediates the effects of acupuncture and that interfering with adenosine metabolism may prolong the clinical benefit of acupuncture.
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              Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies.

              Sheng Han (2002)
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                Author and article information

                Contributors
                rong1215@126.com
                ysg@cdutcm.edu.cn
                tangyong@cdutcm.edu.cn
                peter.illes@medizin.uni-leipzig.de
                Journal
                Purinergic Signal
                Purinergic Signal
                Purinergic Signalling
                Springer Netherlands (Dordrecht )
                1573-9538
                1573-9546
                23 June 2020
                23 June 2020
                September 2020
                : 16
                : 3
                : 297-304
                Affiliations
                [1 ]GRID grid.411304.3, ISNI 0000 0001 0376 205X, International Collaborative Centre on Big Science Plan for Purine Signalling, , Chengdu University of Traditional Chinese Medicine, ; Chengdu, 610075 China
                [2 ]Acupuncture & Chronobiology Key Laboratory of Sichuan Province, Chengdu, 610075 China
                [3 ]GRID grid.9647.c, ISNI 0000 0004 7669 9786, Rudolf Boehm Institute for Pharmacology and Toxicology, , University of Leipzig, ; 04107 Leipzig, Germany
                Article
                9708
                10.1007/s11302-020-09708-z
                7524941
                32577957
                6afb0673-5a83-444f-94c4-3361009b27a7
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 26 March 2020
                : 2 June 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100008402, Chengdu University of Traditional Chinese Medicine;
                Award ID: CZYHW1901
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003512, State Administration of Foreign Experts Affairs;
                Award ID: G20190236012
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100012542, Sichuan Province Science and Technology Support Program;
                Award ID: 2019YFH0108
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © Springer Nature B.V. 2020

                Cell biology
                acupuncture,electroacupuncture,atp,adenosine,p2x receptors,p2y receptors,p1/a1 receptors
                Cell biology
                acupuncture, electroacupuncture, atp, adenosine, p2x receptors, p2y receptors, p1/a1 receptors

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