Peripheral Neuroinflammation and Pain: How Acute Pain Becomes Chronic.

The number of individuals suffering from severe chronic pain and its social and financial impact is staggering. Without significant advances in our understanding of how acute pain becomes chronic, effective treatments will remain out of reach. This mini review will briefly summarize how critical signaling pathways initiated during the early phases of peripheral nervous system inflammation/ neuroinflammation establish long-term modifications of sensory neuronal function. Together with the recruitment of non-neuronal cellular elements, nociceptive transduction is transformed into a pathophysiologic state sustaining chronic peripheral sensitization and pain. Inflammatory mediators, such as nerve growth factor (NGF), can lower activation thresholds of sensory neurons through posttranslational modification of the pain-transducing ion channels transient-receptor potential TRPV1 and TRPA1. Performing a dual role, NGF also drives increased expression of TRPV1 in sensory neurons through the recruitment of transcription factor Sp4. More broadly, Sp4 appears to modulate a nociceptive transcriptome including TRPA1 and other genes encoding components of pain transduction. Together, these findings suggest a model where acute pain evoked by peripheral injury-induced inflammation becomes persistent through repeated cycles of TRP channel modification, Sp4-dependent overexpression of TRP channels and ongoing production of inflammatory mediators.

Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes.

Gene expression is influenced by chromatin architecture via controlled access of regulatory factors to DNA. To better understand gene regulation in the human dorsal root ganglion (hDRG) we used bulk and spatial transposase-accessible chromatin technology followed by sequencing (ATAC-seq). Using bulk ATAC-seq, we detected that in females diverse differentially accessible chromatin regions (DARs) mapped to the X chromosome and in males to autosomal genes. EGR1/3 and SP1/4 transcription factor binding motifs were abundant within DARs in females, and JUN, FOS and other AP-1 factors in males. To dissect the open chromatin profile in hDRG neurons, we used spatial ATAC-seq. The neuron cluster showed higher chromatin accessibility in GABAergic, glutamatergic, and interferon-related genes in females, and in Ca2+- signaling-related genes in males. Sex differences in transcription factor binding sites in neuron-proximal barcodes were consistent with the trends observed in bulk ATAC-seq data. We validated that EGR1 expression is biased to female hDRG compared to male. Strikingly, XIST, the long-noncoding RNA responsible for X inactivation, hybridization signal was found to be highly dispersed in the female neuronal but not non-neuronal nuclei suggesting weak X inactivation in female hDRG neurons. Our findings point to baseline epigenomic sex differences in the hDRG that likely underlie divergent transcriptional responses that determine mechanistic sex differences in pain.