C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception

ABSTRACT: Sensitivity to different pain modalities has a genetic basis that remains largely unknown. The use of closely related inbred mouse strains can facilitate gene mapping of nociceptive behaviors in preclinical pain models. We previously reported enhanced sensitivity to acute thermal nociception in C57BL/6J (B6J) versus C57BL/6N (B6N) substrains. Here, we expanded on pain phenotypes and observed an increase in inflammatory nociceptive behaviors induced by hindpaw formalin injections in B6J versus B6N mice (Charles River Laboratories). No strain differences were observed in mechanical or thermal hypersensitivity or in paw diameter following the Complete Freund s Adjuvant (CFA) model of inflammatory pain, indicating specificity in the inflammatory nociceptive stimulus. In the chronic nerve constriction injury (CCI), a model of neuropathic pain, no strain differences were observed in baseline mechanical threshold or in mechanical hypersensitivity up to one month post-CCI. We replicated the enhanced thermal nociception in B6J mice in the 52.5 C hot plate test relative to B6N mice from The Jackson Laboratory. Using a B6J x B6N-F2 cross (N=164), we mapped a major QTL underlying hot plate sensitivity to chromosome 7 that peaked at 26 Mb (LOD = 3.81, 8.74 Mb-36.50 Mb) that was more pronounced in males. Genes containing expression QTLs (eQTLs) associated with the peak nociceptive marker that have been implicated in pain and inflammation include Ryr1, Cyp2a5, Pou2f2, Clip3, Sirt2, Actn4, and Ltbp4 (FDR < 0.05). Future studies involving positional cloning and gene editing will determine the quantitative trait gene(s) and potential pleiotropy of this locus across other pain modalities. RNA-seq data and genotype information from striatum punches of F2 C57BL/6J (B6J) cross C57BL/NJ (B6NJ) oxycodone-treated mice. Genotypes are given relative to B6J allele, eg 0 = homozygous B6J.

ORGANISM(S): Mus musculus

PROVIDER: GSE119719 | GEO | 2018/11/26

REPOSITORIES: GEO