The Hidden Protein Behind Pain
Single-cell proteomics reveals a key enzyme driving pain sensitization in sensory neurons.
To treat chronic pain, we must understand the individual cells that signal it.
By mapping the proteome of sensory neurons, scientists at the Max Delbrück Center have identified a key enzyme responsible for the way we detect pain.
The hidden language of pain sensation
From the soft brush of a feather to the searing heat of a stove, our bodies rely on a specialized network of sensory neurons located in the dorsal root ganglia. For years, scientists have mapped these cells by looking at their genes, and while this research provided a foundation, gene activity does not always tell the whole story.
Proteins are the functional engines of the cell, yet they have been difficult to study at an individual level.
“Single-cell RNA sequencing of sensory neurons has revealed a molecular basis for such diversity. However, sensory neuron diversity has yet to be captured at the level of the proteome,” said the authors of the new study.
Previously, researchers had to mash up large chunks of tissue to study proteins, called bulk proteomics. This technique blended different cell types together, hiding the unique signals that trigger pain in specific neurons.
“Cell-specific signaling modules can only be accessed by obtaining high-resolution proteomes of single cell types,” said the authors.
Understanding these individual signals is essential for treating conditions such as chronic pain. By using a new, high-resolution mapping technique, the team aimed to identify the specific protein drivers of nociception—the physiological process of detecting harmful stimuli—and create a clearer picture of how our sensory system operates at a molecular level.
Identifying protein markers for pain sensitization
The researchers used a workflow called deep visual proteomics (DVP), which combines electrical recordings of neurons with AI-guided imaging and laser-powered dissection. Ultra-sensitive mass spectrometry is then used to identify the proteins.
By pairing protein analysis with patch-clamp recordings, which measure cell currents, the researchers linked a neuron's electrical activity directly to its unique protein signature.
The team quantified over 6,000 different proteins from various mouse sensory neurons, including those responsible for mechanoreception and pain.
Mechanoreception
Mechanoreception is the biological process by which a cell or organism responds to mechanical stimuli, such as touch, pressure, vibration, or movement, and converts them into electrical signals.
DVP allowed them to quantify up to 3,000 proteins from just one-fourth of a single neuron, revealing subset-specific signatures that were previously invisible.
The study found that mRNA levels often did not match protein levels, suggesting that protein abundance is a much more reliable marker for how a cell behaves.
The team also looked at how these cells change during a pain response. They exposed pain-sensing neurons to inflammatory factors to mimic how the body responds to injury, inducing mechanical sensitization and making the neurons more reactive to touch.
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During this shift, they identified a specific enzyme called B3GNT2, which showed increased levels during sensitization. This increase was found specifically in peptidergic nociceptors, a subtype of neurons heavily involved in transmitting inflammatory pain signals.
Precision medicine for future pain relief
Linking specific proteins to sensory functions provides a new library of targets for treating chronic pain. Currently, many pain medications are broad and cause unwanted side effects. Finding specific markers allows for the development of much more precise therapies that could target pain at its source without affecting other sensations.
“Our dataset offers opportunities to explore the molecular mechanisms underlying nociception, further advancing our understanding of how chronic pain develops and can be prevented,” said the authors.
By knowing exactly which proteins increase during inflammation, scientists can design therapies to block them, moving away from trial-and-error medicine and toward personalized treatments.
However, the study has limitations, such as the proteomic depth in tissue slices; since the tissue sections were so thin, they provided a lower volume of protein than cultured cells. This makes it harder to see low-abundance proteins in an intact environment.
This work will need to be expanded to human samples to ensure that these pain-related proteins function the same as they do in mice. Moving this proteomic map into human biology could finally lead to a new generation of effective pain relief.
Reference: Chakrabarti S, Makhmut A, Mohammadi A, et al. Deep visual proteomics uncovers nociceptor diversity and pain targets. Nat Commun. 2026;17(1):3437. doi: 10.1038/s41467-026-71418-8
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