Alterations in the brain’s μ-opioid receptor (MOR) system have been associated with several neuropsychiatric disorders. Central MOR availability also varies considerably in healthy individuals. ...Multiple epidemiological factors have been proposed to influence the MOR system, but due to small sample sizes the magnitude of their influence remains inconclusive. We compiled 11Ccarfentanil positron emission tomography scans from 204 individuals with no neurologic or psychiatric disorders, and estimated the effects of sex, age, body mass index (BMI) and smoking on 11Ccarfentanil binding potential using between-subject regression analysis. We also examined hemispheric differences in MOR availability. Older age was associated with increase in MOR availability in frontotemporal areas but decrease in amygdala, thalamus, and nucleus accumbens. The age-dependent increase was stronger in males. MOR availability was globally lowered in smokers but independent of BMI. Finally, MOR availability was higher in the right versus the left hemisphere. The presently observed variation in MOR availability may explain why some individuals are prone to develop MOR-linked pathological states, such as chronic pain or psychiatric disorders. Lateralized MOR system may reflect hemispheric work specialization in central emotion and pain processes.
•Sex, age and smoking have regionally specific influence on human μ-opioid receptor (MOR) availability in the brain.•MOR availabilities have regional asymmetries between the two hemispheres, right hemisphere being more abundant in MORs.•Variability in MOR system may explain why some individuals are vulnerable to chronic pain and neuropsychiatric disorders.
Major depressive disorder is associated with lowered mood, anxiety, anhedonia, sleep problems, and cognitive impairments. Many of these functions are regulated by μ-opioid receptor (MOR) system. ...Preclinical, in vivo, and post-mortem studies have however yielded inconclusive results regarding the role of the MOR in depression and anxiety. Moreover, it is not known whether alterations in MOR are already present in subclinical depression and anxiety. In a large-scale retrospective cross-sectional study we pooled data from 135 (113 males and 22 females) healthy subjects whose brain's MOR availability was measured with positron emission tomography (PET) using an agonist radioligand
Ccarfentanil that has high affinity for MORs. Depressive and anxious symptomology was addressed with BDI-II and STAI-X questionnaires, respectively. Both anxiety and depression scores in the subclinical range were negatively associated with MOR availability in cortical and subcortical areas, notably in amygdala, hippocampus, ventral striatum, and orbitofrontal and cingulate cortices. We conclude that dysregulated MOR availability is involved in altered mood and pathophysiology of depression and anxiety disorders.
Abstract
Eating behavior varies greatly between individuals, but the neurobiological basis of these trait-like differences in feeding remains poorly understood. Central μ-opioid receptors (MOR) and ...cannabinoid CB
1
receptors (CB
1
R) regulate energy balance via multiple neural pathways, promoting food intake and reward. Because obesity and eating disorders have been associated with alterations in the brain’s opioid and endocannabinoid signaling, the variation in MOR and CB
1
R system function could potentially underlie distinct eating behavior phenotypes. In this retrospective positron emission tomography (PET) study, we analyzed
11
Ccarfentanil PET scans of MORs from 92 healthy subjects (70 males and 22 females), and
18
FFMPEP-
d
2
scans of CB
1
Rs from 35 subjects (all males, all also included in the
11
Ccarfentanil sample). Eating styles were measured with the Dutch Eating Behavior Questionnaire (DEBQ). We found that lower cerebral MOR availability was associated with increased external eating—individuals with low MORs reported being more likely to eat in response to environment’s palatable food cues. CB
1
R availability was associated with multiple eating behavior traits. We conclude that although MORs and CB
1
Rs overlap anatomically in brain regions regulating food reward, they have distinct roles in mediating individual feeding patterns. Central MOR system might provide a pharmacological target for reducing individual’s excessive cue-reactive eating behavior.
Processing of positron emission tomography (PET) data typically involves manual work, causing inter-operator variance. Here we introduce the Magia toolbox that enables processing of brain PET data ...with minimal user intervention. We investigated the accuracy of Magia with four tracers:
Ccarfentanil,
Craclopride,
CMADAM, and
CPiB. We used data from 30 control subjects for each tracer. Five operators manually delineated reference regions for each subject. The data were processed using Magia using the manually and automatically generated reference regions. We first assessed inter-operator variance resulting from the manual delineation of reference regions. We then compared the differences between the manually and automatically produced reference regions and the subsequently obtained binding potentials and standardized-uptake-value-ratios. The results show that manually produced reference regions can be remarkably different from each other, leading to substantial differences also in outcome measures. While the Magia-derived reference regions were anatomically different from the manual ones, Magia produced outcome measures highly consistent with the average of the manually obtained estimates. For
Ccarfentanil and
CPiB there was no bias, while for
Craclopride and
CMADAM Magia produced 3-5% higher binding potentials. Based on these results and considering the high inter-operator variance of the manual method, we conclude that Magia can be reliably used to process brain PET data.
We aimed to integrate genomic mapping from brain mRNA atlas with the protein expression from positron emission tomography (PET) scans of type 1 cannabinoid (CB1) receptor and to compare the ...predictive power of CB1 receptor with those of other neuroreceptor/transporters using a meta‐analysis. Volume of distribution (VT) from F18‐FMPEP‐d2 PET scans, CNR1 gene (Cannabinoid receptor 1) expression, and H3‐CP55940 binding were calculated and correlation analysis was performed. Between VT of F18‐FMPEP‐d2 PET scans and CNR1 mRNA expression, moderate strength of correlation was observed (rho = .5067, p = .0337). Strong positive correlation was also found between CNR1 mRNA expression and H3‐CP55940 binding (r = .6336, p = .0364), validating the finding between F18‐FMPEP‐d2 PET scans and CNR1 mRNA. The correlation between VT of F18‐FMPEP‐d2 PET scans and H3‐CP55940 binding was marginally significant (r = .5025, p = .0563). From the meta‐analysis, the correlation coefficient between mRNA expression and protein expressions ranged from −.10 to .99, with a pooled effect of .76. In conclusion, we observed the moderate to strong associations between gene and protein expression for CB1 receptor in the human brain, which was validated by autoradiography. We combined the autoradiographic finding with PET of CB1 receptor, producing the density atlas map of CB1 receptor. From the meta‐analysis, the moderate to strong correlation was observed between mRNA expression and protein expressions across multiple genes. Further study is needed to investigate the relationship between multiple genes and in vivo proteins to improve and accelerate drug development.
The moderate to strong associations between gene and protein expression for CB1 receptor in the human brain were observed and we produced the density atlas map of CB1 receptor for the first time in the human brain.
The endogenous mu-opioid receptor (MOR) system modulates a multitude of social and reward-related functions, and exogenous opiates also influence sex drive in humans and animals. Sex drive shows ...substantial variation across humans, and it is possible that individual differences in MOR availability underlie interindividual of variation in human sex drive. We measured healthy male subjects’ (
n
= 52) brain’s MOR availability with positron emission tomography (PET) using an agonist radioligand,
11
Ccarfentanil, that has high affinity for MORs. Sex drive was measured using self-reports of engaging in sexual behaviour (sex with partner and masturbating). Bayesian hierarchical regression analysis revealed that sex drive was positively associated with MOR availability in cortical and subcortical areas, notably in caudate nucleus, hippocampus, and cingulate cortices. These results were replicated in full-volume GLM analysis. These widespread effects are in line with high spatial autocorrelation in MOR expression in human brain. Complementary voxel-based morphometry analysis (
n
= 108) of anatomical MR images provided limited evidence for positive association between sex drive and cortical density in the midcingulate cortex. We conclude that endogenous MOR tone is associated with individual differences in sex drive in human males.
To investigate whether alterations in brain glucose uptake (BGU), insulin action in the brain-liver axis and whole-body insulin sensitivity occur in young adults in pre-obese state.
Healthy males ...with either high risk (HR; n = 19) or low risk (LR; n = 22) for developing obesity were studied with 18Ffluoro-d-glucose (18FFDG)-positron emission tomography during hyperinsulinemic-euglycemic clamp. Obesity risk was assessed according to BMI, physical activity and parental overweight/obesity and type 2 diabetes. Brain, skeletal muscle, brown adipose tissue (BAT), visceral adipose tissue (VAT) and abdominal and femoral s.c. adipose tissue (SAT) glucose uptake (GU) rates were measured. Endogenous glucose production (EGP) was calculated by subtracting the exogenous glucose infusion rate from the rate of disappearance of 18FFDG. BGU was analyzed using statistical parametric mapping, and peripheral tissue activity was determined using Carimas Software imaging processing platform.
BGU was higher in the HR vs LR group and correlated inversely with whole-body insulin sensitivity (M value) in the HR group but not in the LR group. Insulin-suppressed EGP did not differ between the groups but correlated positively with BGU in the whole population, and the correlation was driven by the HR group. Skeletal muscle, BAT, VAT, abdominal and femoral SAT GU were lower in the HR group as compared to the LR group. Muscle GU correlated negatively with BGU in the HR group but not in the LR group.
Increased BGU, alterations in insulin action in the brain-liver axis and decreased whole-body insulin sensitivity occur early in pre-obese state.
Objective
Cannabinoid type 1 receptors (CB1R) modulate feeding behavior and energy homeostasis, and the CB1R tone is dysgulated in obesity. This study aimed to investigate CB1R availability in ...peripheral tissue and brain in young men with overweight versus lean men.
Methods
Healthy males with high (HR, n = 16) or low (LR, n = 20) obesity risk were studied with fluoride 18–labeled FMPEP‐d2 positron emission tomography to quantify CB1R availability in abdominal adipose tissue, brown adipose tissue, muscle, and brain. Obesity risk was assessed by BMI, physical exercise habits, and familial obesity risk, including parental overweight, obesity, and type 2 diabetes. To assess insulin sensitivity, fluoro‐18F‐deoxy‐2‐D‐glucose positron emission tomography during hyperinsulinemic‐euglycemic clamp was performed. Serum endocannabinoids were analyzed.
Results
CB1R availability in abdominal adipose tissue was lower in the HR than in the LR group, whereas no difference was found in other tissues. CB1R availability of abdominal adipose tissue and brain correlated positively with insulin sensitivity and negatively with unfavorable lipid profile, BMI, body adiposity, and inflammatory markers. Serum arachidonoyl glycerol concentration was associated with lower CB1R availability of the whole brain, unfavorable lipid profile, and higher serum inflammatory markers.
Conclusions
The results suggest endocannabinoid dysregulation already in the preobesity state.
Seasonal rhythms influence mood and sociability. The brain μ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains ...elusive with no previously reported
evidence. Here, we first conducted a cross-sectional study with previously acquired human
Ccarfentanil PET imaging data (132 male and 72 female healthy subjects) to test whether there is seasonal variation in MOR availability. We then investigated experimentally whether seasonal variation in daylength causally influences brain MOR availability in rats. Rats (six male and three female rats) underwent daylength cycle simulating seasonal changes; control animals (two male and one female rats) were kept under constant daylength. Animals were scanned repeatedly with
Ccarfentanil PET imaging. Seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability in humans. Brain regions sensitive to daylength spanned the socioemotional brain circuits, where MOR availability peaked during spring. In rats, MOR availabilities in the brain neocortex, thalamus, and striatum peaked at intermediate daylength. Varying daylength also affected the weight gain and stress hormone levels. We conclude that cerebral MOR availability in humans and rats shows significant seasonal variation, which is predominately associated with seasonal photoperiodic variation. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.
Seasonal rhythms influence emotion and sociability. The central μ-opioid receptor (MOR) system modulates numerous seasonally varying socioemotional functions, but its seasonal variation remains elusive. Here we used positron emission tomography to show that MOR levels in both human and rat brains show daylength-dependent seasonal variation. The highest MOR availability was observed at intermediate daylengths. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.
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