Age – sex – gender influence the organization of the brain’s opioid system


Opioids regulate the feelings of pleasure and pain in the brain.

A study by the national Turku PET Centre in Finland shows that age, sex and smoking influence μ-opioid receptor density in the brain.

The results of the study help to better understand the differences between individuals when it comes to neuropsychiatric disorders.

Dysfunctions of the brain’s opioid system are associated with several disorders, such as addiction, and chronic pain problems.

“We noticed in our study that age, sex and smoking have fundamental influence on the organisation of the human brain’s opioid system. This suggests that there are significant differences in the opioid system between individuals, which may explain why some individuals are prone to develop opioid-linked pathological states,” such as psychiatric disorders, explains Tatu Kantonen, Doctor of Medicine.

Brain’s μ-opioid receptors act as important mediators for body’s own opioids in the brain.

This study analysed positron emission tomography (PET) brain scans targeting μ-opioid receptors from 204 individuals with no neurologic or psychiatric disorders. This database was compiled with new computational tools developed at the Turku PET Centre.

“When an opioid molecule binds to a dock-like receptor in the brain, it may cause a feeling of reduced pain or increased pleasure. Putting it more simply, opioids are like the body’s own ambassadors of pleasure and relief,” explains Kantonen.

This shows brain scans from the study
Distribution of μ-opioid receptors in the human brain. Warmer colour stands for more receptors, and colder colour for less receptors. The original image has been published in the NeuroImage. Image is credited to Tatu Kantonen, University of Turku.

Older age was associated with increased μ-opioid receptors in the cerebral cortex, whereas in the deeper parts of the brain they were decreased. The increase in receptors was stronger in males.

Smoking was associated with decreased μ-opioid receptors in most brain regions.

The researchers also discovered that there are more μ-opioid receptors in the right versus the left hemisphere of the brain. This observation may help to explain the previously reported differences between the two hemispheres in the processing of emotions and pain.

The study is based on the AIVO database hosted by Turku University Hospital and Turku PET Centre. The database contains different in vivo molecular brain scans for extensive analyses:

Nicotine, the main bioactive molecule in tobacco, is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system (CNS) including energy homeostasis1–5.

Consequently, nicotine has been demonstrated to decrease food intake through the modulation of hypothalamic neuropeptide systems1,3,5,6.

In addition, nicotine promotes energy expenditure (EE) by activating BAT thermogenesis through a mechanism that involves hypothalamic inhibition of AMP-activated protein kinase (AMPK) and an increase in the sympathetic nervous system (SNS) tone3,7,8.

Current evidence has also pointed to the expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) in white adipose tissue (WAT) during the activation of beige fat and that α2-nAChR increases thermogenesis in UCP1-positive beige adipocytes9.

However, despite these findings, whether nicotine may act centrally to regulate browning of WAT and, more importantly, the mechanisms underlying this effect, remain unclear.

Nicotine can modulate the hedonic/reward pathways, such as the endogenous opioid system 10, which includes the opioid peptides endorphins, enkephalins, dynorphins and endomorphins that act as ligands of the µ, δ, and κ opioid receptors (MOR, DOR, and KOR), a family of G-couple protein receptors that are widely distributed throughout the CNS11–13.

The opioid system has been established as an important regulator in neural hedonic and reward processes, such as those leading to addictive behaviors11,13–15. This is an important issue given the existence of cross addiction, people swapping from one addiction to another, e.g., nicotine to food addiction16.

Notably, current data also point to the opioid system as a homeostatic regulator of energy balance. Naltrexone, an opioid receptor antagonist, is now approved in combination with bupropion for the treatment of obesity17–19.

Moreover, the opioid system has been proposed as a possible target for smoke cessation20,21.

At the central level, the opioid system can act in multiple brain areas. For example, it is known that dynorphin (DYN, an endogenous ligand of KOR) modulates food intake and fat mass by increasing SNS activity22 and that hypothalamic KOR signaling mediates the orexigenic action of ghrelin23 and melanin-concentrating hormone (MCH)24.

In addition, mice lacking MOR, KOR, or DOR resist the development of diet-induced obesity, despite hyperphagia, due to the increased energy expenditure, leading to an overall improvement of the metabolic phenotype25–27.

Based on this evidence, we hypothesized that nicotine’s action on energy homeostasis could be mediated, at least in part, by the opioid signaling.

We found that KOR, specifically in the lateral hypothalamus (LHA), is necessary for nicotine’s action on body weight, BAT thermogenesis and notably browning of WAT.

The clinical relevance of our data is demonstrated by the fact that smokers displayed higher expression of UCP1 in the WAT and a correlation with the smoking status. Our data suggest a previously unknown link between KOR in the LHA in mediating nicotine-induced energy expenditure.

University of Turku


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