The cellular blueprint of chronic pain: New insights from genetic research

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Why look at cells and genes in chronic pain?

We have long known that chronic pain has genetic components, but we did not know which types of brain and nerve cells are influenced by these genetic differences in humans. This study [1] aimed to address that question by combining a large-scale chronic pain genetic dataset with advanced single‑cell analyses of human nervous system tissues. This knowledge can facilitate the development of more effective treatments.

What is unique about this study?

Genetic data from over 1.2 million people were analyzed, identifying hundreds of DNA locations associated with chronic pain. To understand what these genetic signals do, the study compared them with detailed maps of 461 types of brain cells and 16 types of sensory nerve cells from the human dorsal root ganglia (DRG), structures that transmit pain signals from the body to the spinal cord.

DNA vs. gene expression: what is the difference?

Genetic studies look at DNA, which is like a permanent instruction manual we inherit from our parents. But having instructions doesn’t necessarily mean they are being used. Inside each cell, only some genes in the DNA are turned on and make products (so called "transcription"). This is called gene expression. In this study, the DNA findings tell us about genetic differences linked to pain in the inherited genome, while the analyses in brain and nerve cells show which genes are active or switched on in those cells.

From the genetic inheritance (DNA) to the "transcription" or "expression" of a subset of genes that cause a biological effect.

Key findings

• A major finding was that chronic pain genetic risk is especially concentrated in glutamatergic neurons, which are excitatory nerve cells that use the chemical messenger glutamate. Glutamate makes pain pathways hypersensitive, resulting in excessive pain even when injuries are of modest severity (read here about clinical consequences).

• These cells were located in brain regions that help regulate emotion, memory, and decision‑making, including the prefrontal cortex, amygdala, and hippocampus. This confirms that chronic pain involves brain circuits that shape mood, fear, stress, and how pain experiences are stored in the brain (read here about treatment consequences).

• The study also found that a specific pain‑detecting neuron type in the DRG called hPEP.TRPV1/A1.2, a subtype of slow‑conducting C‑fibers, is strongly linked to genetic pain risk. These neurons are known to produce long‑lasting, burning, or emotionally distressing pain sensations.

• Genes linked to chronic pain were often involved in neuronal growth, connectivity, and communication, particularly in pathways governing synapses (the sites of neuronal communication), axon guidance, and neuron‑projection development. These patterns were observed in both brain cells and sensory neurons, suggesting that chronic pain may arise from long‑lasting changes in both the central and peripheral nervous systems.

• The study also looked at tissue samples from patients with acute versus chronic pain and found that several key pain‑associated genes were abnormally active in chronic pain states [2]. This reinforces the idea that chronic pain is not simply prolonged acute pain; it involves distinct biological changes in multiple cell types.

Why this research matters

Overall, this study [1] provides a cellular map associated with chronic pain in the human nervous system. By identifying the cell types and molecular pathways involved, the findings open the door to developing targeted, brain‑ and nerve‑specific treatments for chronic pain, an important step forward given the limitations of current therapies.

References

1. Toikumo S, Parisien M, Leone MJ, Srinivasan C, Yu H, Arendt-Tranholm A, Franco-Enzástiga Ú, Hofstetter C, Curatolo M, Luo W, Pfenning AR, Seal RP, Kember RL, Price TJ, Diatchenko L, Waxman SG, Kranzler HR. The cell-type-specific genetic architecture of chronic pain in brain and dorsal root ganglia. J Clin Invest. 2025 Oct 7;135(24):e197583. doi: 10.1172/JCI197583. PMID: 41055971; PMCID: PMC12700546.

2. Arendt-Tranholm A, Sankaranarayanan I, Payne C, Mancilla Moreno M, Mazhar K, Yap N, Chiu AP, Barry A, Patel PJ, Inturi NN, Tavares-Ferreira D, Amin A, Karandikar M, Jarvik JG, Turner JA, Hofstetter CP, Curatolo M, Price TJ. Transcriptome of the human C2 dorsal root ganglia in C1-2 arthrodesis surgery: insight for neck pain. Brain. 2025 Oct 1:awaf370. doi: 10.1093/brain/awaf370. Epub ahead of print. PMID: 41032656.