The β 3 subunit of the Na +,K +-ATPase mediates variable nociceptive sensitivity in the formalin test

Abstract

It is widely appreciated that there is significant inter-individual variability in pain sensitivity, yet only a handful of contributing genetic variants have been identified. Computational genetic mapping and quantitative trait locus analysis suggested that variation within the gene coding for the β 3 subunit of the Na +,K +-ATPase pump ( Atp1b3) contributes to inter-strain differences in the early phase formalin pain behavior. Significant strain differences in Atp1b3 gene expression, β 3 protein expression, and biophysical properties of the Na +,K + pump in dorsal root ganglia neurons from resistant (A/J) and sensitive (C57BL/6J) mouse strains supported the genetic prediction. Furthermore, in vivo siRNA knockdown of the β 3 subunit produced strain-specific changes in the early phase pain response, completely rescuing the strain difference. These findings indicate that the β 3 subunit of the Na +,K +-ATPase is a novel determinant of nociceptive sensitivity and further supports the notion that pain variability genes can have very selective effects on individual pain modalities.