Discovering the Missing Link in Neuropathic Pain

A key protein, called CSF1, is released from injured nerve cells to cause activation of the immune system, leading to pain in mice. Image (inset): Activated microglia after nerve injury. Credit: Guan et al., 2015. Used with permission from Macmillan Publishers Ltd.

A key protein, called CSF1, is released from injured nerve cells to cause activation of the immune system, leading to pain in mice. Image (inset): Activated microglia after nerve injury. Credit: Guan et al., 2015. Used with permission from Macmillan Publishers Ltd.

Neuropathic pain—the type that results from nerve injury—is one of the most difficult forms of pain to treat in people. Researchers know that after nerve injury, immune cells in the central nervous system called microglia increase in number and become activated, contributing to the onset of neuropathic pain. Yet, the signal that injured nerve cells (neurons) send out that prompts this response from microglia has remained elusive—until now. A new mouse study published online December 7 in the journal Nature Neuroscience reports that the signal is colony-stimulating factor 1 (CSF1), a protein that belongs to a class of signaling molecules known as cytokines.

“We have long known that microglia are involved in the development and maintenance of pain after nerve injury. This new study really elegantly and convincingly fills in the gap about how a nerve tells the spinal cord, and the microglia within it, that an injury has happened,” said Simon Beggs, a pain researcher at the University of Toronto, Canada, who was not involved with the new work.

In the study, researchers led by Zhonghui Guan, Julia Kuhn and Allan Basbaum at the University of California, San Francisco, US, injured the sciatic nerves of mice; this is a commonly used experimental procedure undertaken in animals to learn more about pain. After nerve injury, the animals had a painful increase in sensitivity to mechanical pressure (a phenomenon known as mechanical hypersensitivity).

Then, to identify the molecular signal released by the injured nerves that caused microglia to become activated, the researchers looked at gene expression—which genes were turned on, and which ones were turned off—in response to the nerve injury.

“Hundreds and hundreds of genes changed [after nerve injury],” said Basbaum. The researchers were particularly intrigued to learn that the gene that makes the CSF1 protein was turned on, as was the gene that makes the CSF1 receptor, which is a molecule in microglia to which CSF1 attaches.

“We were struck by this, because they [CSF1 and CSF1 receptor] have long been known to be necessary for the development of microglia,” explained Basbaum. “We found that was worth pursuing,” he added.

Further experiments showed that CSF1 was not present in healthy neurons, but rather was made in injured neurons following nerve injury and transported to the spinal cord. There, CSF1 interacted with the CSF1 receptor.

The researchers also found that CSF1 was both necessary, and sufficient on its own, to activate microglia and cause mechanical hypersensitivity, in the experimental model of nerve injury pain.

Finally, the investigators reported that the activated microglia released another protein, called DAP12, which led to the development of pain.

Overall, the results provide a better understanding of how nerve injury leads to the activation of microglia and pain—and could have relevance to people suffering from chronic pain too, if the same signaling mechanisms are at play. In fact, the results offer the possibility that drugs could be designed that interfere with the signaling between the proteins identified in the study.

“The new findings potentially provide several new [drug] targets—CSF1, CSF1 receptor, and DAP12—that have huge therapeutic potential for neuropathic pain” in people, said Beggs. —Allison Marin.

To read about the research in more detail, see the related Pain Research Forum news story here.

Allison Marin (Curley), PhD, is a neuroscientist-turned-science writer who resides in Pittsburgh, Pennsylvania, US.