Single cell transcriptomics of primate sensory neurons identifies cell types associated with human chronic pain

Abstract

Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of human chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.

Spatial transcriptomics reveals unique molecular fingerprints of human nociceptors

“…A recent study has demonstrated that humans also have Aβ-fiber nociceptors with nociceptive properties (43). The final cluster of A-fibers had high expression of NTRK1 , CPNE6 and SCN10A, which is consistent with Aδ high-threshold mechanoreceptors (HTMRs) in the mouse and macaque (14, 44). This cluster also expressed CALCA and LPAR3 .…”

“…This finding is explained by the expansion of neuronal populations that express HRH1 , the H1 histamine receptor, in human DRG. Interestingly, we do not find expression for most known markers of C-LTMRs in human DRG, including a lack of markers that were recently identified in a nuclear sequencing study from macaques (44), making this population challenging to identify in our study. The exception was GFRA2 expression which marks C-LTMRs across species (16, 23), enabling putative identification of C-LTMRs in human DRG.…”

“…Our findings demonstrate many similarities but also substantial differences between mouse, where most single nociceptor transcriptome work has been done (15, 16, 18). Some of these differences may be explained by technical issues related to sequencing methods, however, our demonstration of more consistent similarities between macaque and human, where different sequencing techniques were also applied (44), makes this possibility less likely. An important outcome of our experiments is the ability to now directly assess target expression across species with single neuron resolution.…”

The impact of C-Tactile Low threshold mechanoreceptors on affective touch and social interactions in mice

“…In vitro calcium imaging in cultured DRG from DREADD expressing mice confirms that most of the neurons functionally responding to DREADD agonist CNO had a unique C-LTMR chemo response pattern consistent with their transcriptional profile regarding the expression of channels and receptors coupled to cytosolic calcium variations. This includes responses to agonists of TRPA1 agonist as reported before 15,16 , as well as to the purinergic metabotropic receptor P2RY1 that is consistently reported to be highly expressed in C-LTMRs across species from rodents to non-human primates 18,20,42,43 . In addition, the CNO responsive neurons where all negative to live staining with fluorescent IB4, as expected from previous studies 15 .…”

How Do Neurons Signal Itch?

“…In humans, classification of primary afferent nociceptors is classically based on their sensory characteristics obtained from single fiber recordings (34)(35)(36)(37)(38), such as mechanical thresholds and temperature sensitivity ( Table 1). Currently, important work is being performed to reduce the translational gaps between rodent and human single cell expression patterns (39,40), but also to link functional characteristics and expression pattern within a single neuron (41). This ongoing work will provide a much more detailed basis for the differentiation between itch and pain processing neurons and the extent of overlap in mediators and receptors.…”