Human sensory neurons exhibit cell-type-specific, pain-associated differences in intrinsic excitability and...

Despite the prevalence of chronic pain, the approval of novel, non-opioid therapeutics has been slow. A major translational challenge in analgesic development is the difference in gene expression and functional properties between human and rodent dorsal root ganglia (DRG) sensory neurons. Extensive work in rodents suggests that sensitization of nociceptors in the DRG is essential for the pathogenesis and persistence of pain; however, direct evidence demonstrating similar physiological sensitization in humans is limited. Here, we examine whether pain history is associated with nociceptor hyperexcitability in human DRG (hDRG). We identified three electrophysiologically distinct clusters (E-types) of hDRG neurons based on firing properties and membrane excitability. Combining electrophysiological recordings and single-cell RNA-sequencing ("Patch-seq"), we linked these E-types to specific transcriptionally defined nociceptor subpopulations. Comparing hDRG neurons from donors with and without evident pain history revealed cluster-specific, pain history-associated differences in hDRG excitability. Finally, we found that hDRG from donors with pain history express higher levels of transcripts encoding voltage-gated sodium channel 1.7 (NaV1.7) and 1.8 (NaV1.8) which specifically regulate nociceptor excitability. These findings suggest that donors with pain history exhibit distinct hDRG electrophysiological profiles compared to those without pain history and further validate NaV1.7 and 1.8 as targets for analgesic development.