Involvement of microglial P2X7 receptors and downstream signaling pathways in long-term potentiation of spinal nociceptive responses |
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| Authors: | Yu-Xia Chu Yan Zhang Yu-Qiu Zhang Zhi-Qi Zhao |
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| Institution: | 1. Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China;2. College of Medicine, Jiaxing University, Jiaxing, Zhejiang Province 314001, China;1. Physiology, School of Medicine, National University of Ireland Galway, University Road, Galway, Ireland;2. Pharmacology and Therapeutics, School of Medicine, National University of Ireland Galway, University Road, Galway, Ireland;3. NCBES Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland Galway, University Road, Galway, Ireland;1. Janssen Research & Development, Neuroscience Therapeutic Area, 3210 Merryfield Row, San Diego, CA 92121, United States;2. Neuroscience External Innovation, Johnson & Johnson Innovation Centre, One Chapel Place, London, W1G 0BG, United Kingdom;1. Departments of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung;2. Department of Anesthesiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;3. Department of Neurosurgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;4. Department of Microbiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;5. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;1. Department of Anesthesiology, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China;2. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China;3. Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, and Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China;4. Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China;5. Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China;6. Department of Pathology, Core Facility of West China Hospital, Chengdu, China;1. Department of Biology, University of Iowa, 369 Biology Building, Iowa City, IA 52242, USA;2. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA;1. Department of Physiology, Information Engineering College of Nanchang University, Nanchang, Jiangxi 330006, PR China;2. Key Laboratory of Basic Medicine, Medical College of Nanchang University, Information Engineering College of Nanchang University, Nanchang, Jiangxi 330006, PR China;3. Department of Biomedical Engineering, Information Engineering College of Nanchang University, Nanchang, Jiangxi 330006, PR China |
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| Abstract: | Tetanic stimulation of the sciatic nerve (TSS) produces long-term potentiation (LTP) of C-fiber-evoked field potentials in the spinal cord. This potentiation is considered to be a substrate for long-lasting sensitization in the spinal pain pathway. Because microglia have previously been shown to regulate the induction of spinal LTP, we hypothesize that P2X7 receptors (P2X7R), which are predominantly expressed in microglia and participate in the communication between microglia and neurons, may play a role in this induction. This study investigated the potential roles of P2X7Rs in spinal LTP and persistent pain induced by TSS in rats. OxATP or BBG, a P2X7R antagonist, prevented the induction of spinal LTP both in vivo and in spinal cord slices in vitro and alleviated mechanical allodynia. Down-regulation of P2X7Rs with P2X7-siRNA blocked the induction of spinal LTP and inhibited mechanical allodynia. Double immunofluorescence showed colocalization of P2X7Rs with the microglial marker OX-42, but not with the astrocytic marker GFAP or the neuronal marker NeuN. Intrathecal injection of BBG suppressed the up-regulation of microglial P2X7Rs and increased expression of Fos in the spinal superficial dorsal horn. Further, pre-administration of BBG inhibited increased expression of the microglial marker Iba-1, phosphorylated p38 (p-p38), interleukin 1β (IL-1β) and GluR1 following TSS. Pre-administration of the IL-1 receptor antagonist (IL-1ra) blocked both the induction of spinal LTP and the up-regulation of GluR1. These results suggest that microglial P2X7Rs and its downstream signaling pathways play a pivotal role in the induction of spinal LTP and persistent pain induced by TSS. |
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