GSE119719
C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception
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. Overall design: C57BL/6J (B6J) and C57BL/NJ (B6NJ) mice were purchased from JAX at 7 weeks of age and were habituated in the vivarium one week prior to experimental testing that occurred next door. B6J females were crossed to B6NJ males to generate B6J x B6NJ-F1 mice and B6J x B6NJ F1 offspring were intercrossed to generate B6J x B6NJ F2 mice. Mice were 50-100 days old at the time of testing. F2 mice recieved four daily oxycodone injections (20 mg/kg, i.p.). Ninety SNP markers spaced approximately 30 Mb (approximately 15 cM) apart were genotyped using a custom-designed Fluidigm array.