Sodium-calcium exchanger-3 regulates pain “wind-up”: From human psychophysics to spinal mechanisms
Teodora Trendafilova, Kaustubh Adhikari, Annina B. Schmid, Ryan Patel, Erika Polgár, Kim I. Chisholm, Steven J. Middleton, Kieran A. Boyle, Allen C. Dickie, Evangelia Semizoglou, Jimena Pérez-Sánchez, Andrew M. Bell, Luis Miguel Ramírez, Samar Khoury, Aleksandar P. Ivanov, Hendrik Wildner, Eleanor Ferris, Juan-Camilo Chacón-Duque, Sophie Sokolow, Mohamed A. Saad Boghdady, 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, Andrés Ruiz‐Linares, David Bennett
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.