Kappa opioid receptor binding in major depression: A pilot study

Abstract

Endogenous kappa opioids mediate pathological responses to stress in animal models. However, the relationship of the kappa opioid receptor (KOR) to life stress and to psychopathology in humans is not well described. This pilot study sought, for the first time, to quantify KOR in major depressive disorder (MDD) in vivo in humans using positron emission tomography (PET). KOR binding was quantified in vivo by PET imaging with the [ C]GR103545 radiotracer in 13 healthy volunteers and 10 participants with current MDD. We examined the relationship between regional [ C]GR103545 total volume of distribution (V ) and diagnosis, childhood trauma, recent life stress, and, in a subsample, salivary cortisol levels during a modified Trier Social Stress Test (mTSST), amygdala, hippocampus, ventral striatum and raphe nuclei. Whole-brain voxel-wise analyses were also performed. [ C]GR103545 V did not differ significantly between MDD participants and healthy volunteers in the four a priori ROIs (p = 0.50). [ C]GR103545 V was unrelated to reported childhood adversity (p = 0.17) or recent life stress (p = 0.56). A trend-level inverse correlation was observed between [ C]GR103545 V and cortisol area-under-the curve with respect to ground during the mTSST (p = 0.081). No whole-brain voxel-wise contrasts were significant. Regional [ C]GR103545 V , a measure of in vivo KOR binding, does not differentiate MDD from healthy volunteers in this pilot sample. Future studies may examine KOR binding in subgroups of depressed individuals at increased risk for KOR abnormalities, including co-occurring mood and substance use disorders, as well as depression with psychotic features.

In Major Depression, Increased Serum Dynorphin and Kappa Opioid Receptor Levels are Positively Associated with Mu Opioid Receptor Levels and Immune Activation and Are Attenuated by Nicotine Dependence

“…The overall conclusion from animal models supports the idea that the KOR system may underpin aspects of sadness and dysphoria but that the cause of the opioid alterations in MDD remains inconclusive (28). Nevertheless, in a pilot study, no differences in KOR binding (using [11C]GR103545) could be found between MDD patients and controls (29), while prodynorphin mRNA was significantly lower in MDD and bipolar depression as compared with controls (30).…”

A Survey of Molecular Imaging of Opioid Receptors

“…This kind of sad reflection provoked greater increases in [ 11 C]Caf ( 8 ) binding in widespread brain regions of women with major depression [189], suggesting an exaggerated opioid response in relation to mood disorder, as distinct from ordinary sadness. A pilot PET study with the κOR-ligand [ 11 C]GR103545 ( 25 ) did not reveal any binding differences between healthy control and patients suffering from major depression [190]. However, a [ 11 C]EKAP ( 27 ) κOR study in healthy volunteers showed an inverse correlation between social status and [ 11 C]salvinorin A ( 33 ) binding in widespread brain areas, with a special association occurring in brain regions mediating reward or aversion [191].…”

Is There a Role for GPCR Agonist Radiotracers in PET Neuroimaging?

“…The first-in-man study was performed in Naganawa et al (2014) and showed the suitability of the tracer for imaging and quantifying kappa receptors in humans, although quantification of kinetic parameters can be difficult due to lack of a reference region and to slow kinetics. Recently, a pilot study of kappa opioid receptor binding in major depression was conducted, using [ 11 C]GR103545 to compare distribution volumes between healthy volunteers and patients suffering from major depressive disorder; no significant differences were detected (Miller et al, 2018). The tracer was also used to investigate the effect of various ligands on the kappa opioid receptor in rodents (Placzek et al, 2015).…”