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      GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats

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          Abstract

          Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive allosteric modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with nalmefene and flumazenil (PNF) in reversing the actions of an anesthetic combination (ketamine-fentanyl-dexmedetomidine, KFD). PAM treatment dose-dependently decreased the duration of the ketamine-induced loss of righting reflex (LORR). Compared with those in the KFD group, the duration of LORR and the analgesic effect of the KFD + PNF group were obviously decreased. Meanwhile, successive administration of PNF and KFD had no adverse effects on the cardiovascular and respiratory systems. Both the KFD group and the KFD + PNF group showed no changes in hepatic and renal function or cognitive function in rats. Moreover, the recovery of motor coordination of the KFD + PNF group was faster than that of the KFD group. In summary, our results suggest the potential application of the PNF combination as an antagonistic treatment strategy for anesthesia.

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          Most cited references 44

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          Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.

          An in situ study of mRNAs encoding NMDA receptor subunits in the developing rat CNS revealed that, at all stages, the NR1 gene is expressed in virtually all neurons, whereas the four NR2 transcripts display distinct expression patterns. NR2B and NR2D mRNAs occur prenatally, whereas NR2A and NR2C mRNAs are first detected near birth. All transcripts except NR2D peak around P20. NR2D mRNA, present mainly in midbrain structures, peaks around P7 and thereafter decreases to adult levels. Postnatally, NR2B and NR2C transcript levels change in opposite directions in the cerebellar internal granule cell layer. In the adult hippocampus, NR2A and NR2B mRNAs are prominent in CA1 and CA3 pyramidal cells, but NR2C and NR2D mRNAs occur in different subsets of interneurons. Recombinant binary NR1-NR2 channels show comparable Ca2+ permeabilities, but marked differences in voltage-dependent Mg2+ block and in offset decay time constants. Thus, the distinct expression profiles and functional properties of NR2 subunits provide a basis for NMDA channel heterogeneity in the brain.
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            The effects of increasing plasma concentrations of dexmedetomidine in humans.

            This study determined the responses to increasing plasma concentrations of dexmedetomidine in humans. Ten healthy men (20-27 yr) provided informed consent and were monitored (underwent electrocardiography, measured arterial, central venous [CVP] and pulmonary artery [PAP] pressures, cardiac output, oxygen saturation, end-tidal carbon dioxide [ETCO2], respiration, blood gas, and catecholamines). Hemodynamic measurements, blood sampling, and psychometric, cold pressor, and baroreflex tests were performed at rest and during sequential 40-min intravenous target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/ml; baroreflex testing only at 0.5 and 0.8 ng/ml). The initial dose of dexmedetomidine decreased catecholamines 45-76% and eliminated the norepinephrine increase that was seen during the cold pressor test. Catecholamine suppression persisted in subsequent infusions. The first two doses of dexmedetomidine increased sedation 38 and 65%, and lowered mean arterial pressure by 13%, but did not change central venous pressure or pulmonary artery pressure. Subsequent higher doses increased sedation, all pressures, and calculated vascular resistance, and resulted in significant decreases in heart rate, cardiac output, and stroke volume. Recall and recognition decreased at a dose of more than 0.7 ng/ml. The pain rating and mean arterial pressure increase to cold pressor test progressively diminished as the dexmedetomidine dose increased. The baroreflex heart rate slowing as a result of phenylephrine challenge was potentiated at both doses of dexmedetomidine. Respiratory variables were minimally changed during infusions, whereas acid-base was unchanged. Increasing concentrations of dexmedetomidine in humans resulted in progressive increases in sedation and analgesia, decreases in heart rate, cardiac output, and memory. A biphasic (low, then high) dose-response relation for mean arterial pressure, pulmonary arterial pressure, and vascular resistances, and an attenuation of the cold pressor response also were observed.
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              Clinical uses of alpha2 -adrenergic agonists.

               T Kamibayashi,  M Maze (2000)
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                Author and article information

                Contributors
                chenyelin@sioc.ac.cn
                jianghongjiuyuan@163.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                24 March 2020
                24 March 2020
                2020
                : 10
                Affiliations
                [1 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Department of Anesthesiology, Shanghai Ninth People’s Hospital, , Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, ; Shanghai, 200011 China
                [2 ]ISNI 0000000119573309, GRID grid.9227.e, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, , Chinese Academy of Sciences, ; Shanghai, 201210 China
                [3 ]ISNI 0000 0004 1797 8419, GRID grid.410726.6, University of Chinese Academy of Sciences, ; Beijing, 100049 China
                [4 ]ISNI 0000 0001 2323 5732, GRID grid.39436.3b, Center for Molecular Imaging, , Shanghai University of Medicine & Health Sciences, ; Shanghai, China
                [5 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Department of Nuclear Medicine, Renji Hospital, School of Medicine, , Shanghai Jiao Tong University, ; 160 Pujian Road, Pudong New District, Shanghai, 200127 China
                [6 ]ISNI 0000 0001 2323 5732, GRID grid.39436.3b, College of Medical Imaging and Shanghai Key Laboratory of Molecular Imaging, , Shanghai University of Medicine and Health Sciences, ; Shanghai, 201318 China
                Article
                62192
                10.1038/s41598-020-62192-8
                7093419
                32210319
                © 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003399, Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission);
                Award ID: 19YF1427700
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100008233, SJTU | School of Medicine, Shanghai Jiao Tong University (School of Medicine, Shanghai Jiao Tong University);
                Award ID: JYZZ047
                Award ID: TM201715
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81901070
                Award ID: 81601536
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100007219, Natural Science Foundation of Shanghai (Natural Science Foundation of Shanghai Municipality);
                Award ID: 19ZR1468600
                Award ID: 17DZ1205403
                Award Recipient :
                Categories
                Article
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                © The Author(s) 2020

                Uncategorized

                disability, pharmacodynamics, preclinical research

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