A high-resolution genomic roadmap for chronic pain converges on glutamatergic neurons and C-fibers
Erick J. Rodríguez-Palma, Rajesh Khanna
Erick J. Rodríguez-Palma, Rajesh Khanna
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Commentary

A high-resolution genomic roadmap for chronic pain converges on glutamatergic neurons and C-fibers

Abstract

Chronic pain etiology involves a shared genetic profile, but its cellular context is poorly defined. In a study published in this issue of the JCI, Toikumo et al. integrated a chronic pain GWAS meta-analysis (n >1.2 million) with single-cell omics data from human brain and dorsal root ganglia. Genetic risk was predominantly enriched in central glutamatergic neurons, particularly those in the prefrontal cortex, hippocampus, and amygdala. In the periphery, the C-fiber nociceptor subtype hPEP.TRPV1/A1.2 was highlighted. Implicated genes converged on involvement in synaptic function and neuron projection development. This work identifies specific central and peripheral cell types that define the genetic architecture of chronic pain, providing a foundation for targeted translational research.

Authors

Erick J. Rodríguez-Palma, Rajesh Khanna

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Figure 1

A genetic roadmap linking the brain and body in chronic pain.

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A genetic roadmap linking the brain and body in chronic pain. Toikumo et...
Toikumo et al. (8) combined genetic data from more than 1.2 million individuals with single-cell transcriptomics and chromatin accessibility analyses from the human brain and DRG. The integrated data were complemented by chromatin accessibility profiling in mouse spinal dorsal horn tissue. These analyses revealed that genetic variants are enriched in glutamatergic neurons of cortico-limbic circuits, C-fiber nociceptors (hPEP.TRPV1/A1.2), and glial cells. Shared genes such as BSN, NCAM1, and NRXN1 connect central and peripheral pathways, showing how genetic susceptibility is distributed across an integrated network. This bidirectional communication between brain and periphery shapes both the emotional-cognitive and sensory aspects of chronic pain.