Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms.

Autor:	Trendafilova T; Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK., Adhikari K; School of Mathematics and Statistics, Faculty of Science, Technology, Engineering and Mathematics, The Open University, Milton Keynes, UK; Department of Genetics, Evolution and Environment, University College London, London, UK; Department of Cell and Developmental Biology, University College London, London, UK., Schmid AB; Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK., Patel R; Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK., Polgár E; School of Psychology and Neuroscience, University of Glasgow, Glasgow, UK., Chisholm KI; Wolfson Centre for Age-Related Diseases, King's College London, London, UK., Middleton SJ; Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK., Boyle K; School of Psychology and Neuroscience, University of Glasgow, Glasgow, UK., Dickie AC; School of Psychology and Neuroscience, University of Glasgow, Glasgow, UK., Semizoglou E; Wolfson Centre for Age-Related Diseases, King's College London, London, UK., Perez-Sanchez J; Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK., Bell AM; School of Psychology and Neuroscience, University of Glasgow, Glasgow, UK., Ramirez-Aristeguieta LM; QST Lab. Faculty of Odontology, Universidad de Antioquia, Medellin, Colombia., Khoury S; McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada., Ivanov A; Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, UK., Wildner H; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland., Ferris E; Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK., Chacón-Duque JC; Department of Genetics, Evolution and Environment, University College London, London, UK; Centre for Palaeogenetics, Stockholm, Sweden; Department of Archaeology and Classical Studies, Stockholm University, Stockholm, Sweden., Sokolow S; Laboratoire de Pharmacodynamie et de Thérapeutique Faculté de Médecine Université Libre de Bruxelles, Brussels, Belgium; School of Nursing, University of California, Los Angeles, Los Angeles, CA, USA., Saad Boghdady MA; Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK., Herchuelz A; Laboratoire de Pharmacodynamie et de Thérapeutique Faculté de Médecine Université Libre de Bruxelles, Brussels, Belgium., Faux P; CNRS, EFS, ADES, Aix-Marseille Université, Marseille, France., Poletti G; Unidad de Neurobiologia Molecular y Genética, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru., Gallo C; Unidad de Neurobiologia Molecular y Genética, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru., Rothhammer F; Instituto de Alta Investigación, Universidad de Tarapacá, Arica, Chile., Bedoya G; GENMOL (Genética Molecular), Universidad de Antioquia, Medellin, Colombia., Zeilhofer HU; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland., Diatchenko L; McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada., McMahon SB; Wolfson Centre for Age-Related Diseases, King's College London, London, UK., Todd AJ; School of Psychology and Neuroscience, University of Glasgow, Glasgow, UK., Dickenson AH; Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK., Ruiz-Linares A; Department of Genetics, Evolution and Environment, University College London, London, UK; CNRS, EFS, ADES, Aix-Marseille Université, Marseille, France; Ministry of Education Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, China. Electronic address: andresruiz@fudan.edu.cn., Bennett DL; Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK. Electronic address: david.bennett@ndcn.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2022 Aug 17; Vol. 110 (16), pp. 2571-2587.e13. Date of Electronic Publication: 2022 Jun 14.
DOI:	10.1016/j.neuron.2022.05.017
Abstrakt:	Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is "wind-up," in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca 2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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