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

Teodora Trendafilova; Kaustubh Adhikari; Annina B Schmid; Ryan Patel; Erika Polgár; Kim I Chisholm; Steven J Middleton; Kieran Boyle; Allen C Dickie; Evangelia Semizoglou; Jimena Perez-Sanchez; Andrew M Bell; Luis Miguel Ramirez-Aristeguieta; Samar Khoury; Aleksandar Ivanov; Hendrik Wildner; Eleanor Ferris; Juan-Camilo Chacón-Duque; Sophie Sokolow; Mohamed A Saad Boghdady; André Herchuelz; Pierre Faux; Giovanni Poletti; Carla Gallo; Francisco Rothhammer; Gabriel Bedoya; Hanns Ulrich Zeilhofer; Luda Diatchenko; Stephen B McMahon; Andrew J Todd; Anthony H Dickenson; Andres Ruiz-Linares; David L Bennett

doi:10.1016/j.neuron.2022.05.017

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

Neuron. 2022 Aug 17;110(16):2571-2587.e13. doi: 10.1016/j.neuron.2022.05.017. Epub 2022 Jun 14.

Authors

Teodora Trendafilova¹, Kaustubh Adhikari², Annina B Schmid¹, Ryan Patel³, Erika Polgár⁴, Kim I Chisholm⁵, Steven J Middleton¹, Kieran Boyle⁴, Allen C Dickie⁴, Evangelia Semizoglou⁵, Jimena Perez-Sanchez¹, Andrew M Bell⁴, Luis Miguel Ramirez-Aristeguieta⁶, Samar Khoury⁷, Aleksandar Ivanov⁸, Hendrik Wildner⁹, Eleanor Ferris¹, Juan-Camilo Chacón-Duque¹⁰, Sophie Sokolow¹¹, Mohamed A Saad Boghdady¹, André Herchuelz¹², Pierre Faux¹³, Giovanni Poletti¹⁴, Carla Gallo¹⁴, Francisco Rothhammer¹⁵, Gabriel Bedoya¹⁶, Hanns Ulrich Zeilhofer¹⁷, Luda Diatchenko⁷, Stephen B McMahon⁵, Andrew J Todd⁴, Anthony H Dickenson³, Andres Ruiz-Linares¹⁸, David L Bennett¹⁹

Affiliations

¹ Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.
² 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.
³ Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
⁴ School of Psychology and Neuroscience, University of Glasgow, Glasgow, UK.
⁵ Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
⁶ QST Lab. Faculty of Odontology, Universidad de Antioquia, Medellin, Colombia.
⁷ McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
⁸ Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, UK.
⁹ Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
¹⁰ 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.
¹¹ 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.
¹² Laboratoire de Pharmacodynamie et de Thérapeutique Faculté de Médecine Université Libre de Bruxelles, Brussels, Belgium.
¹³ CNRS, EFS, ADES, Aix-Marseille Université, Marseille, France.
¹⁴ Unidad de Neurobiologia Molecular y Genética, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru.
¹⁵ Instituto de Alta Investigación, Universidad de Tarapacá, Arica, Chile.
¹⁶ GENMOL (Genética Molecular), Universidad de Antioquia, Medellin, Colombia.
¹⁷ Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
¹⁸ 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.
¹⁹ Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK. Electronic address: david.bennett@ndcn.ox.ac.uk.

Abstract

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 Ca²⁺ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.

Keywords: GWAS; central sensitization; in vivo calcium imaging; in vivo electrophysiology; pain; spinal cord; temporal summation; wind-up.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium*
Humans
Mice
Pain
Posterior Horn Cells
Psychophysics
Sodium-Calcium Exchanger* / genetics

Substances

SLC38A3 protein, human
Slc8a3 protein, mouse
Sodium-Calcium Exchanger
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding