Importin α3 regulates chronic pain pathways in peripheral sensory neurons

Abstract

How is neuropathic pain regulated in peripheral sensory neurons? Importins are key regulators of nucleocytoplasmic transport. In this study, we found that importin α3 (also known as karyopherin subunit alpha 4) can control pain responsiveness in peripheral sensory neurons in mice. Importin α3 knockout or sensory neuron–specific knockdown in mice reduced responsiveness to diverse noxious stimuli and increased tolerance to neuropathic pain. Importin α3–bound c-Fos and importin α3–deficient neurons were impaired in c-Fos nuclear import. Knockdown or dominant-negative inhibition of c-Fos or c-Jun in sensory neurons reduced neuropathic pain. In silico screens identified drugs that mimic importin α3 deficiency. These drugs attenuated neuropathic pain and reduced c-Fos nuclear localization. Thus, perturbing c-Fos nuclear import by importin α3 in peripheral neurons can promote analgesia.

Promoting axon regeneration by enhancing the non-coding function of the injury-responsive coding geneGpr151

“…Among them, we selected Gpr151 as a model gene, an orphan G protein-coupled receptor that mediates nicotine sensitivity and neuropathic pain (Antolin-Fontes et al, 2020; Broms et al, 2015, 2017; Jiang et al, 2018). While Gpr151 upregulation after nerve injury has been reported by several transcriptome studies using DRG tissues 12–16, its role in the regulation of axon regeneration remains unknown (Marvaldi et al, 2020; Shin et al, 2019; Tedeschi et al, 2017; Wlaschin et al, 2018; Wu et al, 2016). We found that Gpr151 mRNA was dramatically upregulated with no changes in the ribosome-association after sciatic nerve injury (Figure 1D).…”

Promoting axon regeneration by enhancing the non-coding function of the injury-responsive coding gene Gpr151

“…Among them, we selected Gpr151 as a model gene, an orphan G protein-coupled receptor that mediates nicotine sensitivity and neuropathic pain 24,26,28,29 . While Gpr151 upregulation after nerve injury has been reported by several transcriptome studies using DRG tissues 12-16, its role in the regulation of axon regeneration remains unknown [30][31][32][33][34] . We found that Gpr151 mRNA was dramatically upregulated with no changes in the ribosomeassociation after sciatic nerve injury ( Figure 1D).…”

β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice

“…von Frey test von Frey tests of sensitivity to mechanical stimuli were conducted as previously described 13 . Briefly, mice were placed in acrylic chambers suspended above a wire mesh grid and allowed to habituate to the testing apparatus for one hour before experimentation.…”

“…[9][10][11] We recently screened a battery of importin a mutant mouse lines for behavioral phenotypes and identified a specific role of importin a5 in anxiety 12 and importin a3 in chronic pain. 13 Importin a5 knockout or specific knockdown in the hippocampus caused a significant reduction of anxiety-related behaviors 12 ; hence, we sought to identify drug candidates that mimic this effect. The connectivity map (CMap) database 14 allows the comparison of transcriptome profiles of interest to gene-expression profiles from cultured human cell lines treated with thousands of clinically approved compounds.…”