NMDA Receptor-Dependent Synaptic Activity in Dorsal Motor Nucleus of Vagus Mediates the Enhancement of Gastric Motility by Stimulating ST36

Evidence-Based Complementary and Alternative Medicine, Oct 2012

Previous studies have demonstrated the efficacy of electroacupuncture at ST36 for patients with gastrointestinal motility disorders. While several lines of evidence suggest that the effect may involve vagal reflex, the precise molecular mechanism underlying this process still remains unclear. Here we report that the intragastric pressure increase induced by low frequency electric stimulation at ST36 was blocked by AP-5, an antagonist of N-methyl-D-aspartate receptors (NMDARs). Indeed, stimulating ST36 enhanced NMDAR-mediated, but not 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic-acid-(AMPA-) receptor-(AMPAR-) mediated synaptic transmission in gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). We also identified that suppression of presynaptic μ-opioid receptors may contribute to upregulation of NMDAR-mediated synaptic transmission induced by electroacupuncture at ST36. Furthermore, we determined that the glutamate-receptor-2a-(NR2A-) containing NMDARs are essential for NMDAR-mediated enhancement of gastric motility caused by stimulating ST36. Taken together, our results reveal an important role of NMDA receptors in mediating enhancement of gastric motility induced by stimulating ST36.

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NMDA Receptor-Dependent Synaptic Activity in Dorsal Motor Nucleus of Vagus Mediates the Enhancement of Gastric Motility by Stimulating ST36

NMDA Receptor-Dependent Synaptic Activity in Dorsal Motor Nucleus of Vagus Mediates the Enhancement of Gastric Motility by Stimulating ST36 Xinyan Gao,1 Yongfa Qiao,2 Baohui Jia,3 Xianghong Jing,1 Bin Cheng,4 Lei Wen,5 Qiwen Tan,4 Yi Zhou,6 Bing Zhu,1 and Haifa Qiao1,4,6 1Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, 16 Nanxiaojie Street, Dongzhimennei, Beijing 100700, China 2Qingdao Haici Medical Group, 4 Renmin Road, Qingdao 266033, China 3Guanganmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China 4The Affiliated Hospital, Shandong University of Traditional Chinese Medicine, Jinan 250014, China 5Department of Pharmacology, Southern Medical University, Guangzhou 510515, China 6Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA Received 12 July 2012; Revised 4 September 2012; Accepted 8 September 2012 Academic Editor: Ying Xia Copyright © 2012 Xinyan Gao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Previous studies have demonstrated the efficacy of electroacupuncture at ST36 for patients with gastrointestinal motility disorders. While several lines of evidence suggest that the effect may involve vagal reflex, the precise molecular mechanism underlying this process still remains unclear. Here we report that the intragastric pressure increase induced by low frequency electric stimulation at ST36 was blocked by AP-5, an antagonist of N-methyl-D-aspartate receptors (NMDARs). Indeed, stimulating ST36 enhanced NMDAR-mediated, but not 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic-acid-(AMPA-) receptor-(AMPAR-) mediated synaptic transmission in gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). We also identified that suppression of presynaptic μ-opioid receptors may contribute to upregulation of NMDAR-mediated synaptic transmission induced by electroacupuncture at ST36. Furthermore, we determined that the glutamate-receptor-2a-(NR2A-) containing NMDARs are essential for NMDAR-mediated enhancement of gastric motility caused by stimulating ST36. Taken together, our results reveal an important role of NMDA receptors in mediating enhancement of gastric motility induced by stimulating ST36. 1. Introduction Gastric motility disorders are clinically characterized by impaired accommodation, gastroparesis, and dumping syndrome. A large number of studies has been conducted to explore the efficacy of somatic stimulation for the treatment of gastrointestinal motility disorders [1–5]. Reproducible results were generated in both clinical and research settings [6, 7], and several lines of evidence suggest that the gastric motility regulation induced by stimulating ST36 seems to be mediated via vagal reflex in the supraspinal pathway [5, 8–10]. However, how stimulating ST36 regulates gastric motility through relay nuclei and the molecular mechanism employed in this process still remain unclear. Addressing this question can provide valuable clues for the development of effective therapeutics against gastrointestinal motility disorders. Vagal motor innervation to the major portion of the gastrointestinal (GI) tract is provided by neurons in the dorsal motor nucleus of the vagus (DMV) [11, 12]. Nucleus of the solitary tract (NTS) neurons can potentially contribute input to the DMV and induce potent effects on vagus-mediated gastric function through excitatory glutamatergic and inhibitory GABAergic synaptic connections [13, 14]. Neuropharmacological studies have demonstrated changes in gastric function in response to localized application of gamma-aminobutyric acid (GABA) and glutamate (via GABAa and NMDA receptors) within the DMV [15–18]. In this study, we directly examined the functional role of NMDAR-mediated synaptic transmission in mediating the upregulation of gastric motility by stimulating ST36. Our data reveal that electroacupuncture at ST36 upregulates gastric motility by specifically enhancing the glutamate-receptor-2a-(NR2A-) containing N-Methyl-D-aspartate-receptors-(NMDAR-) mediated synaptic transmission in gastric-projecting DMV neurons. 2. Materials and Methods2.1. Animals and Surgical Preparation for In Vivo Experiments Adult male Sprague Dawley (250–300 g) rats were purchased from the Institute of Laboratory Animalsciences, CAMS and PUMC (Beijing, China). In this study, all manipulations and procedures were carried out in accordance with The Guide for Care and Use of Laboratory Animals issued by USA National Institutes of Health and were approved by the Institutional Animal Care and Use Committee of China Academy of Chinese Medical Sciences. As described previously [19, 20], rats were housed ( °C) in groups and maintained under a 12 hours light/dark cycle with food and (...truncated)


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Xinyan Gao, Yongfa Qiao, Baohui Jia, Xianghong Jing, Bin Cheng, Lei Wen, Qiwen Tan, Yi Zhou, Bing Zhu, Haifa Qiao. NMDA Receptor-Dependent Synaptic Activity in Dorsal Motor Nucleus of Vagus Mediates the Enhancement of Gastric Motility by Stimulating ST36, Evidence-Based Complementary and Alternative Medicine, 2012, 2012, DOI: 10.1155/2012/438460