TY - JOUR
T1 - Sodium-calcium exchanger-3 regulates pain “wind-up”
T2 - From human psychophysics to spinal mechanisms
AU - Trendafilova, Teodora
AU - Adhikari, Kaustubh
AU - Schmid, Annina B.
AU - Patel, Ryan
AU - Polgár, Erika
AU - Chisholm, Kim I.
AU - Middleton, Steven J.
AU - Boyle, Kieran
AU - Dickie, Allen C.
AU - Semizoglou, Evangelia
AU - Perez-Sanchez, Jimena
AU - Bell, Andrew M.
AU - Ramirez-Aristeguieta, Luis Miguel
AU - Khoury, Samar
AU - Ivanov, Aleksandar
AU - Wildner, Hendrik
AU - Ferris, Eleanor
AU - Chacón-Duque, Juan Camilo
AU - Sokolow, Sophie
AU - Saad Boghdady, Mohamed A.
AU - Herchuelz, André
AU - Faux, Pierre
AU - Poletti, Giovanni
AU - Gallo, Carla
AU - Rothhammer, Francisco
AU - Bedoya, Gabriel
AU - Zeilhofer, Hanns Ulrich
AU - Diatchenko, Luda
AU - McMahon, Stephen B.
AU - Todd, Andrew J.
AU - Dickenson, Anthony H.
AU - Ruiz-Linares, Andres
AU - Bennett, David L.
N1 - Publisher Copyright:
© 2022 The Author(s)
PY - 2022/8/17
Y1 - 2022/8/17
N2 - 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.
AB - 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.
KW - GWAS
KW - central sensitization
KW - in vivo calcium imaging
KW - in vivo electrophysiology
KW - pain
KW - spinal cord
KW - temporal summation
KW - wind-up
UR - https://www.scopus.com/pages/publications/85135841715
U2 - 10.1016/j.neuron.2022.05.017
DO - 10.1016/j.neuron.2022.05.017
M3 - Artículo
C2 - 35705078
AN - SCOPUS:85135841715
SN - 0896-6273
VL - 110
SP - 2571-2587.e13
JO - Neuron
JF - Neuron
IS - 16
ER -