As we shared last week, opioid receptors aren’t just involved in pain relief. They are are a vital aspect to reproduction, growth, weight, respiration, immunological responses, as well as gastrointestinal function and pathophysiology. Opioids and opioid receptors are most often referred to in the mainstream media in terms of their pain relief properties, or the habitual consumption of opioid based pharmaceuticals and the resulting concerns. But to frame opioids and opioid receptors in only that light is to omit their essential role in how the human body functions. Today, we’ll share how some researchers believe that obesity could be targeted by preventing opioids from binding to certain receptors.
To recap from last week, any opioid, whether natural (endogenous) or pharmaceutical (exogenous), fit into opioid receptors. Opioid receptors are found throughout the body, including in the reproductive system, skin, and in the nervous system. Receptors are embedded in the outer membrane of nerve cells (neurons). When opioids bind to the receptors, the interaction triggers a series of chemical changes within and between neurons that lead to feelings of pleasure and pain relief, but not limited to only those sensations. There are five proposed types of opioid receptors (some research institutions and publications recognize Mu, Delta and Kappa as the “main three”), and a variety of subsets of opioid receptors. For the purposes of explaining how opioid receptors impact the body, we’ll focus on the three receptors most often referred to when addressing this topic:
Mu- These are linked to mood, pain and reward. Once activated, these receptors encourage pain relief, elevated mood and respiratory changes. Most exogenous drugs and medications use this pathway.
Delta– It has been postulated that Delta receptors may modulate chronic pain and Mu, acute pain. They also appear to specifically affect a person’s mood, causing anxiety and depression when blocked in mice and mood elevation when activated.
Kappa– These receptors seem to affect not just mood, but reward responses as well, pain relief, increased urination and a profound sense of uneasiness and dissatisfaction with life or dysphoria. The opposite of euphoria.
Numerous rodent studies have shown that shutting down certain opioid receptors can impact energy expenditure, weight, and food intake. Our opioid system appears to interact with systems in our body that ultimately control energy balance and our weight. This opens up exciting new approaches to treating obesity.
How the Mu opioid receptor may impact obesity
We can likely all relate to a situation where we felt satiated after a meal, but another food tempted us to eat more- dessert, for example. This sensation is linked to our evolution- during the times when people were hunter/gatherers, food scarcity could threaten survival and people ate as much calorie-dense food as they could, when it was available. But in the modern era, the availability of food is much different than before, and yet our instinct to continue consuming food has not shifted that drastically. Still, our brains respond to food in a way that encourages us to consume more calories, potentially contributing to the high levels of obesity and consequent health concerns such as type 2 diabetes and cardiovascular disease.
What do opioid receptors have to do with food? Research has focused on a structure in the brain called the “nucleus accumbens”, which sources explain is the “neural interface between motivation and action, playing a key role on feeding, sexual, reward, stress-related, drug self-administration behaviors, etc.”. In studies, when scientists activated the Mu opioid receptor within the nucleus accumbens, animals ate more foods that they found tasty. Interestingly, the animals didn’t appear to be inclined to just eat more generally, but specifically targeted foods. However, when Mu opioid receptors were prevented from binding to opioids, “rats [were] unwilling to respond to a cue to obtain cream, an appetizing, high-fat reward.” And, brain activity that would otherwise typically have prompted the rats to pursue the reward food was non-existent. Researchers highlighted that this effect only occurs in rats that were not hungry. In short, when animals are not hungry, opioid binding in the nucleus accumbens drove them to eat high calorie foods. Knowing this, drugs that target blocking the Mu opioid receptors in the nucleus accumbens may help prevent people from consuming unneeded foods, decrease obesity and related health concerns.
But Kappa and Delta opioid receptors may also play a role in preventing obesity
Research published in The FASEB Journal, shared that blocking the Delta opioid receptor could be another way to help weight loss. In the study, the Delta opioid receptors in mice were blocked, resulting in weight loss, despite being fed a diet high in fat and sugar. “Our study provided further evidence that opioid receptors can control the metabolic response to diets high in fat and sugar, and raise the possibility that these gene products (or their respective pathways) can be targeted specifically to treat excess weight and obesity,” said Traci A. Czyzyk, Ph.D., a researcher involved in the work from the Department of Physiology at the Mayo Clinic in Scottsdale, Arizona.
Another study, published by Cintron-Colon et al. showed that animals exposed to caloric restriction presented a significant decrease in body temperature starting hours after the last meal and showed a 19% decrease in body weight. This is insightful because when calories are readily available, the human body can maintain its core body temperature and also balance heat dissipation; when calories are lacking, the body shifts gears and reduces energy expenditure by lowering the core body temperature to limit weight loss. The researchers ultimately discovered that by blocking the Kappa opioid receptor, which was found to regulate the body’s core temperature shifts, animals could consume fewer calories without their core temperature dropping. This resulted in their energy expenditure maintaining at a higher level, leading to weight loss. These results were not replicated when the Mu and Delta opioid receptors were blocked in the same scenarios.
The potential benefit to these discoveries is that, when combined with lifestyle changes- diet and exercise- obesity and related health concerns could be targeted more effectively with the introduction of a pharmacological opioid suppressant. One source also suggested that this approach could “counteract genetics and related behavioral habits. If successful, this ‘adjuvant’ therapy to diet for those obese people who have co-morbidities, such as diabetes and cardiovascular impairments, could be a life-saver.”
Understanding how the body, including opioid receptors, responds to eating provides a variety of opportunities in addressing obesity and weight management. For some, an initial boost in weight loss with the help of pharmacological intervention associated with opioid receptors may be enough to spring forward on their own when accompanied by establishing healthier lifestyle habits. When maintaining weight loss is more challenging, tools that circumvent the body’s natural inclination to prevent weight loss, by way of knowing how opioid receptors impact weight, may be the ticket to combat obesity.
It’s becoming clearer- what we choose to eat has a significant impact on not only the calories absorbed, but how those foods get metabolized and processed within the body. And in the case of our own opioid system, high fat, calorie dense diets actually alter how they respond, exacerbating weight issues.
Sources:
-https://pubmed.ncbi.nlm.nih.gov/10418795/
-https://www.sciencedirect.com/science/article/pii/S0960982219313673?pes=vor
-https://www.sciencedirect.com/science/article/pii/S0960982219314277
-https://www.healio.com/news/endocrinology/20150629/obesity-weight-loss-impacts-opioid-receptor-activity-in-men
-https://pubmed.ncbi.nlm.nih.gov/10870199/
-https://www.sciencedaily.com/releases/2012/07/120731103054.htm
-https://elifesciences.org/articles/34955
-https://medlineplus.gov/genetics/gene/oprm1/
-https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/dynorphin