Acute Elevations in Cortisol Increase the In Vivo Binding of [11C]NOP-1A to Nociceptin Receptors: A Novel Imaging Paradigm to Study the Interaction Between Stress- and Antistress-Regulating Neuropeptides

Published:September 25, 2019DOI:



      An imbalance between neuropeptides that promote stress and resilience, such as corticotropin-releasing factor and nociceptin, has been postulated to underlie relapse in addiction. The objective of this study was to develop a paradigm to image the in vivo interaction between stress-promoting neuropeptides and nociceptin (NOP) receptors in humans.


      [11C]NOP-1A positron emission tomography was used to measure the binding to NOP receptors at baseline (BASE) and following an intravenous hydrocortisone challenge (CORT) in 19 healthy control subjects. Hydrocortisone was used as a challenge because in microdialysis studies it has been shown to increase corticotropin-releasing factor release in extrahypothalamic brain regions such as the amygdala. [11C]NOP-1A total distribution volume (VT) in 11 regions of interest were measured using a 2-tissue compartment kinetic analysis. The primary outcome measure was hydrocortisone-induced ΔVT calculated as (VT CORT − VT BASE)/VT BASE.


      Hydrocortisone led to an acute increase in plasma cortisol levels. Regional [11C]NOP-1A VT was on average 11% to 16% higher in the post-hydrocortisone condition compared with the baseline condition (linear mixed model, condition, p = .005; region, p < .001; condition × region, p < .001). Independent Student's t tests in all regions of interest were statistically significant and survived multiple comparison correction. Hydrocortisone-induced ΔVT was significantly negatively correlated with baseline VT in several regions of interest.


      Hydrocortisone administration increases NOP receptor availability. Increased NOP in response to elevated cortisol might suggest a compensatory mechanism in the brain to counteract corticotropin-releasing factor and/or stress. The [11C]NOP-1A and hydrocortisone imaging paradigm should allow for the examination of interactions between stress-promoting neuropeptides and NOP in addictive disorders.


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      Linked Article

      • The Complex Role of Nociceptin Signaling in Stress: Clarity Through Neuroimaging?
        Biological PsychiatryVol. 87Issue 6
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          Shortly after it became the first orphan G protein–coupled receptor successfully cloned, the eponymously named nociceptin opioid peptide/orphaninFQ receptor (NOPR) and its endogenous ligand (N/OFQ) were speculated to mediate behaviors beyond nociception (1). Given the high levels of expression of N/OFQ and NOPR in hypothalamic, limbic, and monoaminergic structures across the mammalian brain (2,3), focus quickly turned toward the investigation of how this novel opioidergic system regulated stress and affective behaviors, such as anxiety and depression.
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