King's College London

Research portal

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

Research output: Contribution to journalArticlepeer-review

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 & 13 more 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

Original languageEnglish
Pages (from-to)2571-2587.e13
JournalNeuron
Volume110
Issue number16
Early online date14 Jun 2022
DOIs
Accepted/In press16 May 2022
E-pub ahead of print14 Jun 2022
Published17 Aug 2022

Bibliographical note

Funding Information: We acknowledge the participation of all healthy volunteers in the GWAS. The following funding was received: the Newton Fund Institutional Links Grant from the British Research Council (grant number 216398412 to A.B.S., D.L.B., A.R.-L., and K.A.); the Excellence Initiative of Aix-Marseille University—A ∗ MIDEX (a French ’Investissements d’Avenir' 40 programme to A.R.-L.); the Medical Research Council ( MR/T020113/1 to D.L.B. and S.B.M.; MR/V033638/1 to A.J.T. and K.B.); strategic award from the Wellcome Trust ( 102645/Z/13/Z to A.J.T., D.L.B., A.H.D., and S.B.M. supporting R.P.); Wellcome Trust Senior Scientist Fellowship (ref. no. 095698z/11/z and 202747/Z/16/Z to D.L.B.); Wellcome Investigator Award WT107055AIA (to C.D. Stern supporting K.A.); Wellcome Investigator Award WT219433/Z/19/Z (to A.J.T.); Wellcome Clinical Research Career Development Fellowship 222101/Z/20/Z (to A.B.S.); Wellcome Trust OXION programme (studentship to T.T.); the National Natural Science Foundation of China ( #31771393 ), the Scientific and Technology Committee of Shanghai Municipality ( 18490750300 ), Ministry of Science and Technology of China ( 2020YFE0201600 ), Shanghai Municipal Science and Technology Major Project ( 2017SHZDZX01 ), and the 111 Project ( B13016 ) (to A.R.-L.); and the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) Oxford 5 (supporting A.B.S. and D.L.B.). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding Information: We acknowledge the participation of all healthy volunteers in the GWAS. The following funding was received: the Newton Fund Institutional Links Grant from the British Research Council (grant number 216398412 to A.B.S. D.L.B. A.R.-L. and K.A.); the Excellence Initiative of Aix-Marseille University—A∗MIDEX (a French ’Investissements d'Avenir' 40 programme to A.R.-L.); the Medical Research Council (MR/T020113/1 to D.L.B. and S.B.M.; MR/V033638/1 to A.J.T. and K.B.); strategic award from the Wellcome Trust (102645/Z/13/Z to A.J.T. D.L.B. A.H.D. and S.B.M. supporting R.P.); Wellcome Trust Senior Scientist Fellowship (ref. no. 095698z/11/z and 202747/Z/16/Z to D.L.B.); Wellcome Investigator Award WT107055AIA (to C.D. Stern supporting K.A.); Wellcome Investigator Award WT219433/Z/19/Z (to A.J.T.); Wellcome Clinical Research Career Development Fellowship 222101/Z/20/Z (to A.B.S.); Wellcome Trust OXION programme (studentship to T.T.); the National Natural Science Foundation of China (#31771393), the Scientific and Technology Committee of Shanghai Municipality (18490750300), Ministry of Science and Technology of China (2020YFE0201600), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and the 111 Project (B13016) (to A.R.-L.); and the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) Oxford 5 (supporting A.B.S. and D.L.B.). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Conceptualization, T.T. K.A. A.B.S. S.K. L.D. A.J.T. A.H.D. A.R.-L. S.B.M. and D.L.B.; methodology, T.T. K.A. A.B.S. R.P. E.P. K.B. A.C.D. A.M.B. G.P. C.G. F.R. G.B. H.U.Z. L.D. A.J.T. A.H.D. A.R.-L. K.I.C. E.S. S.B.M. S.J.M. J.P.-S. and D.L.B.; investigation, T.T. K.A. A.B.S. R.P. E.P. K.B. A.C.D. A.M.B. L.M.R.-A. S.K. A.I. H.W. J.-C.C.-D. P.F. S.S. E.F. K.I.C. E.S. S.J.M. J.P.-S. and M.A.S.B.; visualization, T.T. K.A. A.B.S. K.I.C. E.S. S.J.M. and J.P.-S.; funding acquisition, T.T. K.A. A.B.S, A.J.T. A.R.-L. and D.L.B.; project administration, T.T. K.A. A.B.S. R.P. E.P. K.B. A.C.D. A.R.-L. and D.L.B.; writing – original draft, T.T. K.A. A.B.S. R.P. E.P. K.B. A.C.D. A.R.-L. and D.L.B.; writing – review & editing, T.T. K.A. A.B.S. R.P. E.P. K.B. A.C.D. L.M.R.-A. S.K. A.I. H.W. J.-C.C.-D. A.H. G.P. C.G. F.R. G.B. H.U.Z. L.D. A.J.T. A.H.D. A.R.-L. D.L.B. K.I.C. E.S. S.J.M. and J.P.-S. The authors declare no competing interests. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Publisher Copyright: © 2022 The Author(s)

King's Authors

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.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454