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The β3 subunit of the Na+,K+-ATPase mediates variable nociceptive sensitivity in the formalin test

LaCroix-Fralish, Michael L.a; Mo, Garyb; Smith, Shad B.a; Sotocinal, Susana G.a; Ritchie, Jennifera; Austin, Jean-Sebastiena; Melmed, Karaa; Schorscher-Petcu, Arab; Laferriere, Audrey C.a; Lee, Tae Hoona; Romanovsky, Dmitryc; Liao, Guochund; Behlke, Mark A.e; Clark, David J.f; Peltz, Garyg; Séguéla, Philippeb; Dobretsov, Maximc; Mogil, Jeffrey S.a,*

doi: 10.1016/j.pain.2009.04.028
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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 β3 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, β3 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 β3 subunit produced strain-specific changes in the early phase pain response, completely rescuing the strain difference. These findings indicate that the β3 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.

aDepartment of Psychology and Centre for Research on Pain, McGill University, 1205 Dr. Penfield Ave., Montreal, Que., Canada H3A 1B1

bDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, and Centre for Research on Pain, McGill University, Montreal, Que., Canada H3A 2B4

cDepartment of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA

dDepartment of Genetics and Genomics, Roche Palo Alto, Palo Alto, CA 94304, USA

eIntegrated DNA Technologies Inc., Coralville, IA 52241, USA

fDepartment of Anesthesiology, Stanford University, Palo Alto, CA 94304, USA

gDepartment of Anesthesia, Stanford University, Stanford, CA 94305, USA

*Corresponding author. Tel.: +1 514 398 6085; fax: +1 514 398 4896.

E-mail address:jeffrey.mogil@mcgill.ca

ARTICLE INFO

Article history:

Received January 23, 2009

Received in revised form April 9, 2009

Accepted April 28, 2009.

© 2009 Lippincott Williams & Wilkins, Inc.
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