Title
Sodium-calcium exchanger-3 regulates pain “wind-up”: From human psychophysics to spinal mechanisms
Date Issued
17 August 2022
Access level
open access
Resource Type
journal article
Author(s)
Trendafilova T.
Adhikari K.
Schmid A.B.
Patel R.
Polgár E.
Chisholm K.I.
Middleton S.J.
Boyle K.
Dickie A.C.
Semizoglou E.
Perez-Sanchez J.
Bell A.M.
Ramirez-Aristeguieta L.M.
Khoury S.
Ivanov A.
Wildner H.
Ferris E.
Chacón-Duque J.C.
Sokolow S.
Saad Boghdady M.A.
Herchuelz A.
Faux P.
Gallo C.
Rothhammer F.
Bedoya G.
Zeilhofer H.U.
Diatchenko L.
McMahon S.B.
Todd A.J.
Dickenson A.H.
Ruiz-Linares A.
Bennett D.L.
Publisher(s)
Cell Press
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.
Start page
2571
End page
2587.e13
Volume
110
Issue
16
Language
English
OCDE Knowledge area
Neurociencias
Subjects
Scopus EID
2-s2.0-85135841715
PubMed ID
Source
Neuron
ISSN of the container
08966273
Sponsor(s)
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.
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.
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