Pain and depression often go hand in hand. In fact, more than half of chronic pain patients become depressed and anxious, and patients with depression are more likely to develop chronic pain following an injury. But little is known about the genes and brain regions underlying the links between the two disorders.
Now, a team of scientists in New York City has scanned the entire genome of mice with chronic pain from nerve injury to uncover thousands of genes altered in brain areas responsible for both pain and depression. Analyzing the function of each of these genes and how they might work together, the group has developed a large list of potential therapeutic targets—the genes, and the proteins they produce, that drugs could act against —and biological systems for researchers to explore.
“This intersection [between pain and depression] is becoming a major interest in my group,” says Venetia Zachariou, Icahn School of Medicine at Mount Sinai, New York, US, who led the team. “The more information we collect, the easier it will be for us to identify entirely new targets for pain and pain-related depression,” said Zachariou,
The work was published online March 21 in the journal Science Signaling.
Pain gives rise to depression
People with chronic pain are very likely to also develop depression. Intuitively this makes sense since individuals suffering from pain are often under immense emotional stress. Interestingly, drugs that help the depression accompanying chronic pain also help treat the underlying pain itself. And, some of the brain regions involved in chronic pain are also involved in depression, including the nucleus accumbens, prefrontal cortex and periaqueductal gray (PAG), areas well known to pain researchers. This led Zachariou to ask whether there might be a genetic basis for the pain-depression connection.
The team came up with a simple approach. In one group of mice, they created long-lasting chronic pain by severing two nerve branches in the leg, a common method followed in experimental studies of pain. In another group of mice, they produced depression by exposing the animals to stressful situations such as removing their food or restraining them.
Then, the researchers measured changes in gene expression—which genes are turned on or off—in the three brain regions. This allowed them to generate two lists of genes—those altered in the mice with pain, and those modified in the mice with depression—that could then be compared to one another.
Remarkably, several genes were modified in both groups of mice. The investigators then compared the genes they identified to a massive online database containing information about the functioning of genes, their interactions with one another, and their associations with other disorders. This allowed them to identify important genes and the biological activities they control.
Two interesting patterns emerged from this analysis. HDAC5, a protein involved in regulating how genes function, interacted with many of the genes that were significantly changed in two of the three brain regions.
Following up on this finding, the researchers found that mice genetically engineered to lack HDAC5 still experienced pain from the experimental nerve injury but didn’t experience depression. This suggested that HDAC5 played a role in the emotional aspects, but not the painful aspects of the nerve injury model used in the study.
A second pattern emerged from looking at genes with the highest changes in gene expression. Of those genes, calpain-11, which makes a protein that degrades other proteins, was significantly increased in all three brain regions examined in the research.
The researchers then found that inhibiting calpain-11 with a drug for two weeks reduced pain in the nerve-injured mice, but had no effect on depression. This indicated that calpain-11 controlled the painful, but not emotional features present after nerve injury.
The hope is that the genes identified in the study will serve as a roadmap for researchers throughout the fields of pain and depression. They will have a lot of work to do, combing through each gene one by one in hopes of finding new ways to treat patients.
“There’s quite a lot in this paper. It’s a huge dataset so the interpretation of the results is going to take a long time for us to put together,” said Sandrine Géranton, a pain researcher at University College London, UK, who was not involved in the study.
To read about the research in more detail, see the related Pain Research Forum news story here.
Nathan Fried is a postdoctoral fellow at the University of Pennsylvania, Philadelphia, US.