Trendafilova, T. et al. (2022) Sodium-calcium exchanger-3 regulates pain "wind-up": from human psychophysics to spinal mechanisms. Neuron, 110(16), 2571-2587.e13. (doi: 10.1016/j.neuron.2022.05.017) (PMID:35705078) (PMCID:PMC7613464)
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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 Ca efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.
| Item Type: | Articles |
|---|---|
| Keywords: | GWAS, pain, in vivo electrophysiology, in vivo calcium imaging, spinal cord, temporal summation, central sensitization, wind-up. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Boyle, Dr Kieran and Bell, Mr Andrew and Beresford-Polgar, Dr Erika and Todd, Professor Andrew and Dickie, Dr Allen |
| Creator Roles: | Polgár, E.Methodology, Investigation, Project administration, Writing – original draft, Writing – review and editing Boyle, K.Methodology, Investigation, Project administration, Writing – original draft, Writing – review and editing Dickie, A. C.Methodology, Investigation, Project administration, Writing – original draft, Writing – review and editing Bell, A. M.Methodology, Investigation Todd, A. J.Conceptualization, Methodology, Funding acquisition, Writing – review and editing |
| Authors: | 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., Poletti, G., Gallo, C., Rothhammer, F., Bedoya, G., Zeilhofer, H. U., Diatchenko, L., McMahon, S. B., Todd, A. J., Dickenson, A. H., Ruiz-Linares, A., and Bennett, D. L. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
| Journal Name: | Neuron |
| Publisher: | Elsevier (Cell Press) |
| ISSN: | 0896-6273 |
| ISSN (Online): | 1097-4199 |
| Published Online: | 14 June 2022 |
| Copyright Holders: | Copyright © 2022 The Authors |
| First Published: | First published in Neuron 110(16): 2571-2587.e13 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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