An analysis of gene activity in pain neurons could help identify the most promising drug targets and reveal how pain pathways differ between men and women
16 February 2022
Chronic pain, defined as that lasting 12 weeks or more, affects between one-third and a half of all adults in the UK. Globally, about 70 per cent of the people it impacts are women. With the world’s population getting older, finding new treatments and therapies is becoming more urgent because chronic pain is more prevalent in older groups.
“A lot of pain studies have been conducted in mice and there’s been some lack of translation when it comes to looking for drug targets for humans,” says Diana Tavares-Ferreira at the University of Texas at Dallas.
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To learn more about the differences between species, she and her team mapped the pain neurons in eight deceased people who had donated their bodies to science and then compared these findings with data from mice and macaques.
Pain signals are carried by specialised neurons with fibres that spread throughout the body, but the main parts of these cells are in clusters called dorsal root ganglia.
“Many pain drug development projects are focused on targeting these peripheral neurons,” says Theodore Price at the University of Texas at Dallas, a co-author of the study. “These neurons are the source of pain for most chronic pain patients.”
The team used a method called spatial transcriptomics to determine which genes are active in each cell. This showed that pain receptors in humans seem to be geared to respond to all kinds of pain, such as heat or mechanical pain, whereas rodent pain receptors are more specific.
Learning more about these differences will help in the pursuit of drug candidates that are more likely to work in humans, says Price. “This is hopefully the start of many studies which produce more atlases that help us better understand the molecular architecture of the pain system in humans,” he says.
The team also looked at sex differences in the human samples. “We found that there’s probably more differences in the underlying mechanisms that promote chronic pain between male and female humans compared to sex differences in rodent models,” says Price.
For example, the gene that encodes the protein CGRP was more active in clusters of neurons from women compared with men. “CGRP seems to be a major driver of migraines and migraines affect women three times as much as men,” says Price.
It is important to overcome our lack of knowledge on which proteins distinguish different pain receptors, says Peter McNaughton at King’s College London.
“Deciphering the critical proteins involved in generating different types of pain would be a considerable advance towards developing drugs to suppress chronic pain,” he says. “This study is among the first to use human sensory neurons. It is certain to act as a reference work – a sensory neuron atlas – for years to come.”
However, pain neurons aren’t the whole story. Earlier this month, another study, which has yet to be peer-reviewed, showed that another type of cell, called a Schwann cell, may play an important role in pain and touch perception, in addition to its better-known role of providing insulation around nerve fibres.
Gary Lewin at the Max Delbrück Center for Molecular Medicine in Berlin, Germany, and his colleagues genetically engineered mice so that a specific type of Schwann cell in their skin could be controlled using light. They found that Schwann cells were just as important to mechanical pain perception and touch as any sensory neuron in the mice.
“This study is exciting because it suggests we’ve missed a large proportion of what might actually be happening [in pain perception],” says Lewin. “No one’s been looking for pain therapy targets in this area.” Lewin is confident that Schwann cells will play a similar role in humans, but it is unclear what role they may play in chronic pain.
Although maps of sensory neurons won’t tell us everything we need to know about pain, Lewin says they are a good start. “They give us the tools to ask questions about what we should be targeting [with pain medication],” he says.
Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.abj8186