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Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response

Recla, Jill M.a,b,*; Bubier, Jason A.a; Gatti, Daniel M.a; Ryan, Jennifer L.a; Long, Katie H.a; Robledo, Raymond F.a; Glidden, Nicole C.c; Hou, Guoqianga; Churchill, Gary A.a; Maser, Richard S.a; Zhang, Zhong-weia; Young, Erin E.c,d,e; Chesler, Elissa J.a; Bult, Carol J.a

doi: 10.1097/j.pain.0000000000001571
Research Paper

Identification of genetic variants that influence susceptibility to pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with persistent pain, we measured late-phase response to formalin injection in 275 male and female Diversity Outbred mice genotyped for over 70,000 single nucleotide polymorphisms. One quantitative trait locus reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus, Nociq4 (nociceptive sensitivity quantitative trait locus 4; MGI: 5661503), harbors the well-known pain gene Trpa1 (transient receptor potential cation channel, subfamily A, member 1). Trpa1 is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of Diversity Outbred founder strain allele effects revealed a significant effect of the CAST/EiJ allele at Trpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the 7 other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants in Trpa1 by assessing channel conductance, TRPA1-TRPV1 interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained by Trpa1 isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.

A single polymorphism in Trpa1 was found to specifically affect late-phase responding on the formalin test by altering allele-specific expression in Diversity Outbred mice.

aThe Jackson Laboratory, Bar Harbor, ME, United States

bIGERT Program in Functional Genomics, Graduate School of Biomedical Sciences and Engineering, The University of Maine, Orono, ME, United States

cDepartment of Genetics and Genome Sciences, UCONN Health, Farmington, CT, United States

dSchool of Nursing, University of Connecticut, CT, United States

eInstitute for Systems Genomics, University of Connecticut, Storrs, CT, United States

Corresponding author. Address: 600 Main St, Bar Harbor, ME 04609, United States. Tel.: 207-288-6408. E-mail address: (J.M. Recla).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received July 05, 2018

Received in revised form March 01, 2019

Accepted March 04, 2019

Online date: March 27, 2019

© 2019 International Association for the Study of Pain
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