Rats' counterintuitive responses to sugar and opioids suggests a complex connection

May 3, 2021
High-fructose corn syrup affects the way rats process opioids. (AP Photo/Matt Rourke)

High-fructose corn syrup affects the way rats process opioids. (AP Photo/Matt Rourke)

Researchers studying rats have discovered that consuming high-fructose corn syrup alters their response to oxycodone in several contradictory ways, strengthening some aspects of the drug response while dampening others.

The study, published April 15 in Pharmacology Biochemistry and Behavior, complicates the understanding of the link between opioids and nutrition, which could offer insight into conditions such as opioid abuse and obesity.

"It is known that the hedonic aspects of food consumption," said senior author Francesco Leri, referring to when people eat purely for pleasure, "is highly mediated by opioid receptors of the opioid system in the brain." Leri is a professor of psychology at the University of Guelph, in Canada, where he and his team study the effects of chemical stimuli on cognitive processes.

Opioids are among the most powerful painkillers, which has made them incredibly useful as therapeutics, particularly for the 20.5% of U.S. adults suffering from chronic pain. But opioid abuse is also a growing public health crisis. According to the National Institutes of Health, 21% to 29% of patients who are prescribed an opioid shift into abusive use, and 80% of people who use heroin begin by abusing prescription opioids.

A connection between sugar and opioids is well-established, to the point where naltrexone, a drug that helps prevent opioid relapse, is now prescribed to treat obesity. This connection has emerged because both sugar and drugs are associated with pleasure and reward systems in the brain.

However, many studies about sugar and opioids focus on overconsumption. To fill this gap, the researchers developed a way to let the rats in the experiment decide how much sugar they were going to consume when given access to it.

"Everything really began when we adopted a model to study drug intake, which is essentially a self-administration procedure that has an open component," Leri said.

Because the rats had access to both food and sugar, they were less likely to overconsume.

"When they start drinking the sugar, they eat less food, so they balance the two so that they don't [become] dysregulated," Leri said. "They don't become obese. It's not addictive behavior at all."

After the rats lived with access to high-fructose corn syrup for a full 26 days, a standard length of time for sugar studies of this type, they were given doses of oxycodone, one of the most prescribed opiates.

To study the response to the drug, the researchers tested place preference, or the tendency to remember and return to the place where a stimulus occured. They also tested the rats' locomotion and the levels of dopamine in the brain.

Leri and the team hypothesized that if there were an interaction between opioids and high-fructose corn syrup, it would come in one of two forms. The first option would be sensitization, where "exposure to one stimulus sensitizes the organism to another stimulus," meaning that rats would experience more severe effects of opioids when they had eaten sugar.

The other expected response would be habituation, the scientific term for tolerance, in which repeated exposure to stimuli reduces their effect. In this case, the rats would experience dampened effects from opioids.

"We got a mix of the two," Leri said.

In other words, when compared with rats that had received only oxycodone, sugar made some effects of the drug more intense, and others less so.

The rats experienced enhanced place preference for oxycodone, meaning that they repeatedly returned to where they had received their dose. They also experienced more severe suppression of locomotion.

However, Leri explained that opioids do not only suppress locomotion. They usually have a biphasic effect that at first inhibits locomotion but later stimulates it. In this case, though, the stimulation phase never came.

"We found that the animals that were exposed to sugar were more sensitive to the suppression caused by the opioids, but their response to the psychomotor simulation part of the curve wasn't changed," Leri said.

The levels of dopamine in the brain were counterintuitive as well. Opioids generally cause large spikes in dopamine.

"The size of the spike was reduced in our animals," Leri said. "We were expecting to see the opposite."

The findings suggest that while high-fructose corn syrup clearly has some sort of interaction with oxycodone, that interaction is much more complex than a simple sensitization or habituation. And while the findings add to a body of knowledge about sugar and opioids, Leri warns that there are far too many unanswered questions to instantly extrapolate them to humans.

"There's so many factors that play a role in human drug addiction. And some of these factors now are getting related to other life factors in nutrition," he said. "It's not just one of those things that will be like, 'Well, yeah. It's what you eat, we're sure.'"

The study, "High fructose corn syrup alters behavioral and neurobiological responses to oxycodone in rats," published April 15 in PNAS, was authored by Meenu Minhas, Cheryl L. Limebeer, Evan Strom, Linda A. Parker and Francesco Leri, University of Guelph.

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