Study links anorexia nervosa to elevated opioid receptor levels in brain’s reward centers

A new neuroimaging study published in Molecular Psychiatry provides evidence that anorexia nervosa is associated with altered activity in the brain’s opioid system. Women with anorexia had higher levels of mu-opioid receptor availability in key areas of the brain involved in reward processing, such as the caudate, putamen, and nucleus accumbens. Interestingly, these changes occurred without any difference in brain glucose metabolism between anorexia patients and healthy controls, suggesting a specific disruption in the neural pathways that regulate motivation and pleasure.

Anorexia nervosa is a serious psychiatric condition marked by extreme food restriction, intense fear of gaining weight, and a distorted perception of one’s body. The disorder most commonly begins during adolescence and primarily affects women. Anorexia is associated with a wide range of health complications, including organ damage, hormonal imbalance, and in severe cases, death. It also has the highest mortality rate of any psychiatric illness.

Current treatments focus on restoring weight, improving body image, and changing disordered eating habits through a combination of psychotherapy, nutrition counseling, and sometimes medication. But many patients struggle with relapse or chronic symptoms, and the underlying biology of the disorder remains poorly understood.

The research team conducted the study to investigate whether changes in the brain’s endogenous opioid system might help explain the symptoms of anorexia. The mu-opioid receptor, a key part of this system, plays a role in both the regulation of hunger and the experience of pleasure from food. Previous studies have shown that activation of this receptor increases food intake and that its availability is altered in obesity. But until now, relatively little was known about its involvement in anorexia.

To explore this question, the researchers recruited 13 women with anorexia nervosa and 13 healthy women of similar age. All participants were screened through a series of physical and psychiatric evaluations. The women with anorexia were underweight and had been diagnosed within the past two years. None of the participants had a history of other psychiatric disorders or conditions that could affect metabolism or brain function.

Each participant underwent two types of brain imaging using positron emission tomography, or PET scans. One scan used a radiolabeled compound that binds to mu-opioid receptors, allowing the researchers to measure how available those receptors were in different parts of the brain. The other scan measured how the brain uses glucose, the body’s main energy source, during a controlled infusion of insulin and glucose known as a hyperinsulinemic-euglycemic clamp. This technique allowed the researchers to assess brain glucose uptake under conditions that mimic normal metabolism. Participants also completed a functional magnetic resonance imaging (fMRI) scan while viewing images of appetizing and bland foods to assess emotional responses to food cues.

The results showed that the availability of mu-opioid receptors was significantly higher in several brain areas associated with reward, including the caudate and putamen. The nucleus accumbens and thalamus also showed trends toward higher receptor availability, although these did not remain statistically significant after correcting for multiple comparisons. These findings suggest that the opioid system in people with anorexia may be hyperactive or hypersensitive in specific regions involved in processing reward and motivation.

Interestingly, there was no difference in brain glucose uptake between the two groups, indicating that basic brain metabolism remains stable despite severe weight loss. However, the researchers found a negative correlation between opioid receptor availability and glucose uptake in several of the same brain regions. In other words, individuals with higher mu-opioid receptor availability tended to have lower glucose use in those areas. This relationship may point to a compensatory mechanism that allows the brain to maintain energy efficiency while adapting to changes in the reward system.

In the fMRI portion of the study, there was no significant difference in how patients and controls responded to pictures of palatable versus bland food. The researchers noted that this may be due to the small sample size or individual differences in food preferences that were not directly measured.

Taken together, the findings suggest that people with anorexia nervosa may experience changes in how their brains process the reward value of food. The mu-opioid receptor system, which normally encourages eating by making food feel pleasurable, may function differently in these individuals. Higher receptor availability could reflect an attempt by the brain to compensate for reduced hedonic responses to eating, or it might play a role in the initial development of food avoidance behavior.

This altered reward response may help explain why individuals with anorexia often find eating distressing rather than pleasurable, even when they are severely undernourished. It also raises the possibility that targeting the opioid system with medication could one day be a strategy to help treat the disorder.

The study has several strengths. It is the first to use a combination of two advanced PET imaging techniques to examine both receptor availability and glucose metabolism in the same individuals. The use of a highly controlled insulin-clamp protocol also provided more precise estimates of brain metabolism than traditional methods.

However, the study also has limitations. It included only women, so the results may not apply to men with anorexia. The sample size was small, partly due to the challenges of recruiting participants for such an intensive imaging study. The researchers also did not collect detailed data on participants’ eating behavior during the study, which limits the ability to directly link brain differences to specific symptoms. Lastly, because the study was cross-sectional, it cannot determine whether changes in the opioid system are a cause or a consequence of anorexia.

The study, “Anorexia nervosa is associated with higher brain mu-opioid receptor availability,” was authored by Kyoungjune Pak, Jouni Tuisku, Henry K. Karlsson, Jussi Hirvonen, Eleni Rebelos, Laura Pekkarinen, Lihua Sun, Aino Latva-Rasku, Semi Helin, Johan Rajander, Max Karukivi, Pirjo Nuutila, and Lauri Nummenmaa.