A damaged nerve can give rise to pain that endures for months, years, or even a lifetime. Why pain becomes chronic is a key question that pain researchers continue to grapple with. One line of thought says that if pain endures, then there must also be long-lasting changes, at the level of cells and molecules, to accompany it.
Now, using an established nerve injury model of chronic pain in mice, a new study suggests just that, by showing that enduring changes to the “epigenome”—the set of chemical modifications to DNA that determines which genes are turned on or off in an organism—may keep cells called microglia “primed” to contribute to future pain. Microglia are considered the immune cells of the central nervous system (spinal cord and brain), and are known to contribute to chronic pain (see related RELIEF news story).
“For the first time, the authors have identified injury-induced, long-lasting changes in the epigenome,” in a model of chronic pain, says Sandrine Géranton, who studies the role of the epigenome in chronic pain at University College London, UK, but was not involved in the new work.
The new research was published May 24 in the journal Cell Reports.
Primed for pain?
In the study, Franziska Denk and colleagues at King’s College London, UK, examined mice that had surgery to injure the sciatic nerve—a common experimental model used to study the pain system in animals—and compared them to animals without such damage.
A week after the surgery, the researchers saw that more than a dozen genes were turned on in microglia isolated from the spinal cord of injured mice, compared to their uninjured counterparts. And, at the same time, these cells were left with molecular footprints or “marks”–36 in total–in the epigenome. Specifically, the group identified a chemical modification made to histones, which are proteins around which DNA wraps, in the cells.
They also found that many of these molecular footprints were found near regulatory regions of DNA called “enhancers,” which are known to influence which genes are expressed over time scales as long as a cell’s lifetime.
Of most interest, when the investigators checked the microglia about a month after nerve injury, they saw that the changes in which genes were turned on in nerve-injured animals had vanished. Yet, out of eight histone marks the researchers had preselected to examine, a few were still there. That contrast suggested to Denk that these changes in the epigenome may not keep pain going once it starts. Instead, the marks could prime microglia for later pain, making them more likely to react in a harmful way during the pain signaling process. “The microglia are not quite in the right state, and so if you activated them again they could respond worse than before,” she says.
Trying to definitively prove whether or not the molecular footprints identified in the current study contribute to chronic pain is technically difficult at the moment, as researchers lack a good experimental toolbox to do so. In the meantime, Denk wants to know whether the long-lasting changes in microglia also exist in spinal cord neurons that transmit pain signals, and which can become hypersensitive after a nerve injury. Géranton thinks this is likely the case, as “we know that many cell types contribute to the development of chronic pain states.”
Regardless, Denk sees the current study as “a proof of principle—that you can have long-lasting epigenomic changes as a result of a chronic pain state.” – Matthew Soleiman
To read about the research in more detail, see the related Pain Research Forum news story here.
Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman