As anyone living with chronic pain can attest, the condition amounts to much more than an unpleasant physical sensation. Chronic pain has wide-ranging effects on the brain, leading to disruptions of thought, memory, sleep and mood. Researchers are working to understand what happens in the brain to cause those disruptions, and whether they can be reversed.
A recent mouse study led by Ted Price of the University of Texas at Dallas now shows that cognitive deficits arising from neuropathic pain (pain from nerve injury) can be reversed by metformin, a drug widely prescribed to treat diabetes.
Surprisingly, the cognitive deficits were far greater in male than in female mice, suggesting that different processes in the nervous system may be at work in males vs. females during chronic pain. The researchers also saw striking changes in the brain following neuropathic pain in male but not female animals.
Marco Martina, a pain researcher at Northwestern University in Chicago who was not involved in the work, called it “a well-done study that addresses the critical question, ‘What underlies the cognitive deficits in chronic pain?’ It opens up some new ideas about the underpinnings, and it provides further proof that very quickly with the development of a pain condition you have major morphological changes in the brain,” referring to changes in the structure of nerve cells.
The work was published in the Journal of Neuroscience on August 15.
A model to test cognition in mice
Why do a study on pain and cognition in the first place?
“Chronic pain patients taking pain relievers still experience cognitive deficits,” said the study’s lead author, Stephanie Shiers, also of the University of Texas at Dallas. “You would think that if you get rid of the pain, you would get rid of conditions that accompany chronic pain, such as depression and anxiety, but that’s not the case. That’s why we tried to tackle the issue.”
In order to study the effects of chronic pain on cognitive function in mice, Shiers and the team used a model of neuropathic pain called spared nerve injury (SNI). Here, mice receive a surgery that causes damage to portions of the sciatic nerve, but without harming surrounding tissue. Several weeks later, the animals become very sensitive to two common tests to assess pain in animals: mechanical pokes with a thin filament, and cold temperature, each applied to the paw.
The researchers next needed a way to test the effects of chronic pain on cognition. So they borrowed a model from collaborator Sven Kroener, also of the University of Texas at Dallas, who was using it to study schizophrenia and addiction in animals. The model uses what’s called an attentional set-shifting task, which measures mental flexibility.
For the task, mice were trained to use one strategy—in this case, to always turn left or always turn right in a maze to locate a Cheerio treat. During training, “there is also a visual cue that they have to ignore,” Shiers said.
The mice learned the task before receiving the SNI surgery, and three weeks after surgery when the mice were retested, they remembered the task. The following day, the mice were tested again, but they had to change their strategy in order to find the treat.
“The ‘switch’ part is that they have to turn toward the visual cue,” rather than relying on the strategy they initially learned. “They have to get rid of their perseverance and be flexible to a new strategy. Mice with neuropathic pain took significantly longer to learn that new rule” than mice without nerve injury, Shiers said.
“We were all stunned at the size of the effect,” Price said of the finding. “It’s absolutely massive.” Surprisingly, though, the cognitive deficit was only seen in male mice, so the researchers focused the rest of their experiments on male animals.
Some drugs work but not others
The researchers wanted to determine whether each of three pain relievers could ease the animals’ compromised mental flexibility.
Clonidine, a drug for high blood pressure also used to treat pain, alleviated hypersensitivity to paw pokes in the nerve-injured mice, but had no effect on the set-shifting task. Treatment with a different drug used to treat pain, gabapentin, also eased the hypersensitivity, but mice performed even worse on the cognitive task after treatment.
“With clonidine and gabapentin, given either immediately after injury for a short time or long-term, we didn’t see any improvement in the cognitive impairment, so temporary relief of pain is not sufficient” to reverse cognitive deficits, Shiers said.
After male mice were treated daily with metformin for a week, however, both the hypersensitivity and cognitive deficits seen in mice with nerve injury were similar to normal animals.
“We believe that metformin may be what’s called disease modifying,” Shiers said. This means that the drug may reverse or ease processes at the molecular level that underlie chronic pain, rather than simply damp down pain. Much remains to be learned about this, “but however metformin is working, it’s restoring cognitive function,” she added.
Changes in the brain
Brain imaging studies have shown over the past decade that the brain rapidly undergoes major changes in structure and function in people with chronic pain. But studies in animals are necessary to understand what explains those changes and find ways to counteract them with new drugs.
Shiers and her colleagues homed in on a part of the brain called the medial prefrontal cortex (mPFC), where cognitive deficits arise. They saw two types of changes in the mPFC of male mice with neuropathic pain.
First, the number of neurons containing a protein called parvalbumin (PV) was reduced compared to normal mice or to female animals with nerve injury.
Second, the neurons of male mice with SNI had a shorter axon initial segment (AIS). The AIS is a part of the neuron that extends and retracts and is key to the electrical signaling function of nerve cells.
Both changes could reflect what happens when there is too much electrical activity in neurons in the mPFC, which is a sign of cognitive impairment, Shiers said.
Of the two types of brain changes the researchers saw, the loss of the PV neurons was reversed with gabapentin treatment, but not with metformin. That hints that those neurons might not be at the heart of the cognitive disruption. The AIS length, however, was restored by seven-day treatment with metformin but not with gabapentin.
An old drug for a new purpose?
How is it that a cheap drug widely prescribed for diabetes works to alleviate chronic pain from nerve injury?
“It’s been known for a long time that metformin has benefits for the heart and brain separate from its effects on blood glucose,” Price said. “Our study adds to the cadre of work showing that, at least in males, it has powerful effects on neuropathic pain. The cognitive disruption goes back to normal, and it seems to be affecting neurons at the structural level.”
“I’d love to say we know how metformin works, and it will be important to figure it out, because the clues are there to get to new therapeutics,” he added.
Will the findings from mice apply to people?
“Molecularly yes,” said Price, “but there’s a huge disconnect in the dose we use in our studies and what’s given to humans for diabetes—there’s no question about that.” But figuring out how metformin is functioning could allow it to be repurposed to treat pain.
“If metformin could be safely given to people for chronic pain, it could be remarkably effective, and it’s been right under our nose the whole time,” he said.
To read about the research in more detail, see the related Pain Research Forum news story here.
Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD