The Targetable Human Nociceptome: 300-Plex Spatial Transcriptomics in Human Dorsal Root Ganglion (DRG) for Analgesic Discovery

Authors

• SR Shah
• MR Sapio
• O Blivis
• MJ Iadarola
• AJ Mannes

Abstract

Recent studies have defined a population of primary afferent sensory neurons inhibited by clinically useful analgesics that are critical for pain control. These neurons express nociceptive markers such as transient receptor potential vanilloid 1 (TRPV1) and the mu-opioid receptor (OPRM1) which makes them noci-responsive and sensitive to opioids. We have recently defined many of the marker genes of these neurons using published single cell RNA-Seq datasets in combination with anatomical investigations using highly sensitive 4-plex in situ hybridization. However, the limited number of concurrent molecular labels creates a challenge for cataloguing targetable receptors in fine detail. Using a Xenium 300-plex panel of marker genes and targetable receptors together, we examined human dorsal root ganglion to achieve a better understanding of the targetable receptors. In order to make this technique successful in DRG, we adapted the protocol by using alternative segmentation in a previously published method, Baysor, which outperformed the default segmentation for this tissue. Using this data, we confirmed previous investigations suggesting that the kappa opioid receptor (OPRK1) is primarily expressed in satellite glial cells and not DRG neurons, and extended these investigations to novel findings. One example was the identification of the understudied regulator of G-protein signaling 4 (RGS4) with TRPV1, and its strong expression in several neuronal populations relevant to pain. This gene has previously been associated with altered sensory thresholds. These data unlock a foundational understanding of targetable signaling molecules in human DRG, allowing for detailed inferences on the potential validity of past, current, and future analgesics.

Scientific Focus Area: Neuroscience

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