By now, most people realize that diet can have a dramatic influence on health. From diabetes to heart disease and even cancer, poor diet can be a major risk factor, whereas a healthy diet reduces the likelihood of those conditions. But what about chronic pain?
Recent evidence suggests that diet can indeed influence pain conditions (see RELIEF related podcast.) In November 2017, tens of thousands of researchers gathered in Washington, DC, at the annual meeting of the Society for Neuroscience (SfN), the world’s largest neuroscience conference for scientists and physicians seeking to understand the brain and nervous system (see RELIEF related SfN coverage). Among them were young researchers presenting their latest findings on the links between diet and pain.
Research examining the connection between nutrition and pain at the molecular level focuses mainly on polyunsaturated fatty acids (PUFAs), which are plentiful in the diet and serve important roles in the immune and other biological systems in people. Some PUFAs can promote or lessen inflammation. Omega-3 PUFAs, found in fish and nuts, for example, are anti-inflammatory, whereas omega-6 PUFAs, found in processed and fried foods, can tip the body’s balance toward inflammation, a process known to worsen chronic pain.
Omega-6 turns up the heat
Jacob Boyd, a graduate student in the lab of Ken Hargreaves at the University of Texas Health Science Center in San Antonio, US, presented research suggesting that high dietary levels of the pro-inflammatory omega-6 PUFAs increase the risk for pain in mice. They do so by boosting activity at a protein, called TRPV1, that is found in pain-sensing neurons and detects hot temperatures, as well as capsaicin—the component of chili peppers that makes them “hot.” A related protein, TRPA1, is activated by mustard oil, cold temperatures and many other unpleasant and potentially harmful substances, and is also present in pain-sensing cells.
Recent research has shown that metabolites of omega-6 PUFAs can activate TRPV1 and TRPA1. Boyd hypothesized that a diet rich in pro-inflammatory omega-6 PUFAs might lead to increased pain by interacting with these proteins.
To test this idea, mice were fed their usual diet, or food containing five or ten percent omega-6 PUFAs. Boyd measured how long the animals took to withdraw their paw from a hot plate or a poke with a filament (both common experimental tests used to test pain sensitivity in animals) at the beginning of the experiment and again after 15 weeks on the diet. Mice fed their usual diet saw no change in withdrawal time from the hotplate. But mice on the 10 percent omega-6 diet showed a significant decrease in withdrawal time—indicating they had become more sensitive to pain. Diet did not affect the response to the filaments.
Boyd repeated the tests in mice fed the usual, five percent or ten percent omega-6 diet. This time he did so after injecting the paw with an inflammatory substance, another common method in pain research that provides a model of inflammatory pain. Here, too, in the hours following the injury, mice fed the high-omega-6 diet were far more sensitive to heat, but not the filaments.
Boyd then injected the paws of uninjured mice with capsaicin or mustard oil to activate TRPV1 or TRPA1, respectively, and tracked the animals’ responses, including lifting, shaking and licking the paw, three “pain-related” behaviors in the animals thought to indicate discomfort. Mice fed the high omega-6 diet showed significantly more of these responses than those fed their normal diet, in response to capsaicin, though not to mustard oil. That finding suggests that dietary omega-6 could influence pain via TRPV1 but not TRPA1. Boyd cautioned, however, that whether this is true cannot be understood just by watching how the animals behave; researchers must also perform other experiments at the molecular level to confirm it.
If omega-6 PUFAs increase pain sensitivity, could the anti-inflammatory omega-3 PUFAs reduce it? Daiany Redivo, from Federal University of Parana, Curitiba, Brazil, presented her work in the lab of Joice Maria Cunha testing the effects of omega-3 PUFAs on pain from nerve injury (neuropathic pain) in rats with an experimental form of diabetes. Much like human patients, the rats develop painful neuropathy. Accordingly, they display allodynia—pain sensitivity to stimuli that are not normally painful—which is a hallmark of neuropathy.
Two weeks after producing diabetes in the rats, Redivo began supplementing the animals’ diet with either fish oil—rich in omega-3 PUFAs—or with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), the two major omega-3 PUFAs found in fish oil. She then measured the force it took for rats to withdraw their paw from a poke with a filament.
In the hours after an acute treatment with omega-3, the animals’ withdrawal threshold increased compared to untreated diabetic rats, meaning that they could tolerate a stronger mechanical poke. This effect lasted for about two hours.
After two weeks of daily omega-3 treatment, rats that received the highest dose of fish oil, EPA or DHA had a mechanical withdrawal threshold similar to that of healthy rats without diabetes, whereas the pain threshold continued to fall, indicating increased pain sensitivity, in untreated diabetic rats. Redivo is now working to identify the specific molecules that EPA and DHA affect to reduce neuropathic pain.
American diet shifts the microbiome—how SAD
In 2017, Robert Sorge of the University of Alabama, Birmingham, US, showed that a Standard American Diet (with the apt acronym, SAD)—high in carbohydrates, fats and omega-6 PUFAs—delayed recovery after an experimental injury in mice that causes inflammation. Animals were fed the SAD, a regular diet (REG), or an Anti-Inflammatory Diet (AID) packed with known anti-inflammatory foods and healthy omega-3 PUFAs. Mice fed the SAD grew fatter. After the injury, the SAD mice took twice as long to recover as the mice on REG, whereas animals on AID recovered several days sooner.
Unfortunately, mice that ate the REG or AID during the week and were allowed to consume the SAD on weekends—like many people do—were no better off than those who ate SAD all week. (To read about the research in more detail, see related IASP Pain Research Forum news story here.)
At the SfN meeting, graduate student Stacie Totsch, who works in Sorge’s lab, provided an update to those findings, along with some hints about the roots of these dietary effects on pain. In looking for a link between food and inflammation, Totsch turned to the microbiome, which is made up of all the bacteria found in the gut. The microbiome has been gaining ground as a key connection between diet and the immune system, and it has now been implicated in diseases ranging from diabetes to Alzheimer’s.
Totsch examined the bacterial species in the mouse gut and found that animals fed the AID had more of a broad category of bacteria called actinobacteria—what Totsch called “good bacteria.” Mice fed the SAD diet, in contrast, harbored more proteobacteria, which potentially can be harmful.
Bacteroidetes is another broad category of bacteria affected by the diet. “Bacteroidetes, a major population of bacteria found in the healthy gut, was significantly decreased with the SAD diet,” Totsch said, perhaps because “the gut’s living space is taken up by more harmful bacteria.”
Can sweeteners change the brain’s response to pain drugs?
Finally, a separate line of research looked at how high-fructose corn syrup can change the way the brain responds to opioid. Millions of people are regularly prescribed opioids in the US, and people react very differently to the drugs, with some becoming addicted while others do not.
“One factor we think might affect people’s responses to opioids is certain foods,” said Meenu Minhas, presenting her work as a graduate student from the lab of Francesco Leri at the University of Guelph, Ontario, Canada, during a press conference highlighting research on opioids.
Sugars act on the brain’s reward system, much like opioid drugs and other rewarding substances do. Minhas and her colleagues fed rats either sugar-free water or a 50% solution of high-fructose corn syrup for 26 days. After nine days without sugar, Minhas then tested the responses of the animals to a dose of oxycodone, an opioid widely prescribed for pain.
As expected, rats increased their movement following the dose of oxycodone, but this response was blunted in the rats that had been fed the sweetener. The researchers then measured brain levels of dopamine, a key neurotransmitter that conveys reward, after rats had received oxycodone. The amount of dopamine released in response to oxycodone was blunted in the brains of rats raised on the sweetener compared to those on sugar-free water. The results show that high-fructose corn syrup alters the brain’s response to oxycodone, both in terms of the animals’ behavior and neurotransmitter production in the brain. This suggests that the drug may not be as rewarding in animals fed the sweetener, potentially increasing the risk of addiction.
In another experiment called conditioned place preference, rats learn to spend more time in a place where they receive something rewarding. In Minhas’s experiment, rats spent more time where they received oxycodone than in another location. Feeding the sweetener did not affect conditioned place preference, though, suggesting that the animals found the drug rewarding regardless of their sugar exposure. That finding, Minhas later told RELIEF in an email, “indicates that not all aspects of the addictive properties of oxycodone are affected by pre-exposure to high-fructose corn syrup.”
Together, Minhas said, the results suggest that a diet high in high-fructose corn syrup may increase the abuse potential of opioid drugs.
“These findings can inform policy,” according to Minhas. For example, policymakers “may want to decrease high-fructose corn syrup intake by increasing taxes, regulating advertising, and educating individuals,” she said.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.