Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test

Abstract

Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation.

Social transfer of alcohol withdrawal-induced hyperalgesia in female prairie voles

“…As an alternative interpretation, two potential scenarios can be theorized: an experimenter would not notice a deviation from threshold baseline due to repeated testing in the H 2 0/Separate group or would notice a non-existent decrease in threshold in the H 2 0/Co-Housed group. Our analysis of the limited hyperalgesia literature that mentions the terms “baseline” and “von Frey” in the publication abstracts identifies no deviation from baseline due to repeated testing across multiple mouse strains and in rats (Banik, Woo, Park, & Brennan, 2006; Macolino, Daiutolo, Albertson, & Elliott, 2014; E. E. Young et al, 2016).…”

Gene Transcript Alterations in the Spinal Cord, Anterior Cingulate Cortex, and Amygdala in Mice Following Peripheral Nerve Injury

“…In contrast, the amounts of GPCR histamine receptor H1R ( Huang et al, 2017 ) and G protein-coupled receptor 35 (Gpr35) ( Cosi et al, 2011 ) in the spinal cord ( Figure 3A ), Grm5 ( Ramos-Prats et al, 2019 ) in the ACC ( Supplementary Figure 2A ), and Gpr35 ( Savitz et al, 2015 ) and Lpar1 ( Pedraza et al, 2014 ; González de San Román et al, 2019 ) in the AMY ( Supplementary Figure 3A ) were dramatically decreased after SNL. For the ion channels, we observed the observably elevated expression of Cacna2d2 ( Yu et al, 2019 ), Orai1 ( Dou et al, 2018 ), Aqp9 ( Wu et al, 2020 ), and Trpc6 ( Jin et al, 2017 ; Wang et al, 2020 ) in the spinal cord ( Figure 3A ), Gria1 ( Toyoda et al, 2009 ) and Cacna1c ( Jeon et al, 2010 ) in the ACC ( Supplementary Figure 2B ), and Cacna1c ( Temme and Murphy, 2017 ), Cacna2d1 ( Chen et al, 2018 ; Young et al, 2016 ), and Trpc6 ( Jin et al, 2017 ; Wang et al, 2020 ) in the AMY ( Supplementary Figure 3B ) after SNL. On the contrary, significant reductions were seen in the levels of ion channel transcripts for Kcnq5 ( Manville and Abbott, 2018 ), Cacna1b ( Stevens et al, 2019 ), and Kcnj6 ( Zheng et al, 2015 ) in the spinal cord ( Figure 3B ), Gabrb3 ( Tripp et al, 2012 ), Gabra1 ( Chandley et al, 2015 ), and Grik2 ( Chandley et al, 2015 ) in the ACC ( Supplementary Figure 2B ), as well as the downregulation of the ion channels such as Scn1a, Ano1, Cacna1h ( Gangarossa et al, 2014 ), Cacna1d ( McKinney et al, 2009 ), and Gabra1 ( Guilloux et al, 2012 ) in the AMY ( Supplementary Figure 3B ) on day 7 after SNL.…”

The pain trajectory of juvenile idiopathic arthritis (JIA): translating from adolescent patient report to behavioural sensitivity in a juvenile animal model

“…Here we show that the relationship between high pain and prior arthritic activity is dependent on this sensitivity. Individual pain sensitivities in rodents have been described elsewhere, focussing on genetic differences between rodent strains [25–27] or between sexes [28]. Individual differences in the response to acute noxious stimuli in rats of the same strain have been reported previously, [29, 30] but differences in the pain behaviour trajectories following joint inflammation has not.…”