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

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

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.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Fysiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Physiology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
central sensitization
GWAS
in vivo calcium imaging
in vivo electrophysiology
pain
spinal cord
temporal summation
wind-up
calcium
sodium calcium exchange protein
animal
genetics
human
mouse
posterior horn cell
psychophysics
Animals
Humans
Mice
Posterior Horn Cells
Sodium-Calcium Exchanger

Adhikari, Kaustubh (author)
Schmid, Annina B. (author)
Patel, Ryan (author)
Polgár, Erika (author)
Chisholm, Kim I. (author)
Middleton, Steven J. (author)
Boyle, Kieran (author)
Dickie, Allen C. (author)
Semizoglou, Evangelia (author)
Perez-Sanchez, Jimena (author)
Bell, Andrew M. (author)
Ramirez-Aristeguieta, Luis Miguel (author)
Khoury, Samar (author)
Ivanov, Aleksandar (author)
Wildner, Hendrik (author)
Ferris, Eleanor (author)
Chacón-Duque, Juan-CamiloStockholms universitet,Institutionen för arkeologi och antikens kultur,University College London, UK(Swepub:su)cach0137 (author)
Sokolow, Sophie (author)
Saad Boghdady, Mohamed A. (author)
Herchuelz, André (author)
Faux, Pierre (author)
Poletti, Giovanni (author)
Gallo, Carla (author)
Rothhammer, Francisco (author)
Bedoya, Gabriel (author)
Zeilhofer, Hanns Ulrich (author)
Diatchenko, Luda (author)
McMahon, Stephen B. (author)
Todd, Andrew J. (author)
Dickenson, Anthony H. (author)
Ruiz-Linares, Andres (author)
Bennett, David L. (author)
Stockholms universitetInstitutionen för arkeologi och antikens kultur (creator_code:org_t)

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Physiology

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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