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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:https://doi.org/10.1016/j.biopsych.2019.09.013

      Abstract

      Background

      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.

      Methods

      [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.

      Results

      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.

      Conclusions

      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.

      Keywords

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      References

        • Ciccocioppo R.
        • de Guglielmo G.
        • Hansson A.C.
        • Ubaldi M.
        • Kallupi M.
        • Cruz M.T.
        • et al.
        Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: Significance for anxiety-like behaviors.
        J Neurosci. 2014; 34: 363-372
        • Green M.K.
        • Devine D.P.
        Nociceptin/orphanin FQ and NOP receptor gene regulation after acute or repeated social defeat stress.
        Neuropeptides. 2009; 43: 507-514
        • Zhang Y.
        • Simpson-Durand C.D.
        • Standifer K.M.
        Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder.
        Br J Pharmacol. 2015; 172: 571-582
        • Reiss D.
        • Wolter-Sutter A.
        • Krezel W.
        • Ouagazzal A.M.
        Effects of social crowding on emotionality and expression of hippocampal nociceptin/orphanin FQ system transcripts in mice.
        Behav Brain Res. 2007; 184: 167-173
        • Narendran R.
        • Tollefson S.
        • Himes M.L.
        • Paris J.
        • Lopresti B.
        • Ciccocioppo R.
        • et al.
        Nociceptin receptors upregulated in cocaine use disorder: A positron emission tomography imaging study using [(11)C]NOP-1A.
        Am J Psychiatry. 2019; 176: 468-476
        • Narendran R.
        • Tollefson S.
        • Fasenmyer K.
        • Paris J.
        • Himes M.L.
        • Lopresti B.
        • et al.
        Decreased nociceptin receptors are related to resilience and recovery in college women who have experienced sexual violence: Therapeutic implications for posttraumatic stress disorder.
        Biol Psychiatry. 2019; 85: 1056-1064
        • Cook C.J.
        Glucocorticoid feedback increases the sensitivity of the limbic system to stress.
        Physiol Behav. 2002; 75: 455-464
        • Koob G.F.
        Corticotropin-releasing factor, norepinephrine, and stress.
        Biol Psychiatry. 1999; 46: 1167-1180
        • Schwartz M.L.
        • Tator C.H.
        • Hoffman H.J.
        The uptake of hydrocortisone in mouse brain and ependymoblastoma.
        J Neurosurg. 1972; 36: 178-183
        • Ciccocioppo R.
        • Fedeli A.
        • Economidou D.
        • Policani F.
        • Weiss F.
        • Massi M.
        The bed nucleus is a neuroanatomical substrate for the anorectic effect of corticotropin-releasing factor and for its reversal by nociceptin/orphanin FQ.
        J Neurosci. 2003; 23: 9445-9451
        • Ciccocioppo R.
        • Biondini M.
        • Antonelli L.
        • Wichmann J.
        • Jenck F.
        • Massi M.
        Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198.
        Psychopharmacology (Berl). 2002; 161: 113-119
        • Ciccocioppo R.
        • Martin-Fardon R.
        • Weiss F.
        • Massi M.
        Nociceptin/orphanin FQ inhibits stress- and CRF-induced anorexia in rats.
        Neuroreport. 2001; 12: 1145-1149
        • Ciccocioppo R.
        • Cippitelli A.
        • Economidou D.
        • Fedeli A.
        • Massi M.
        Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect.
        Physiol Behav. 2004; 82: 63-68
        • Rodi D.
        • Zucchini S.
        • Simonato M.
        • Cifani C.
        • Massi M.
        • Polidori C.
        Functional antagonism between nociceptin/orphanin FQ (N/OFQ) and corticotropin-releasing factor (CRF) in the rat brain: evidence for involvement of the bed nucleus of the stria terminalis.
        Psychopharmacology (Berl). 2008; 196: 523-531
        • Nazzaro C.
        • Barbieri M.
        • Varani K.
        • Beani L.
        • Valentino R.J.
        • Siniscalchi A.
        Swim stress enhances nociceptin/orphanin FQ-induced inhibition of rat dorsal raphe nucleus activity in vivo and in vitro: role of corticotropin releasing factor.
        Neuropharmacology. 2010; 58: 457-464
        • Martins J.M.
        • Kastin A.J.
        • Banks W.A.
        Unidirectional specific and modulated brain to blood transport of corticotropin-releasing hormone.
        Neuroendocrinology. 1996; 63: 338-348
        • Merchenthaler I.
        Corticotropin releasing factor (CRF)-like immunoreactivity in the rat central nervous system.
        Extrahypothalamic distribution. Peptides. 1984; 5: 53-69
        • Potter E.
        • Behan D.P.
        • Linton E.A.
        • Lowry P.J.
        • Sawchenko P.E.
        • Vale W.W.
        The central distribution of a corticotropin-releasing factor (CRF)-binding protein predicts multiple sites and modes of interaction with CRF.
        Proc Natl Acad Sci U S A. 1992; 89: 4192-4196
        • Witta J.
        • Palkovits M.
        • Rosenberger J.
        • Cox B.M.
        Distribution of nociceptin/orphanin FQ in adult human brain.
        Brain Res. 2004; 997: 24-29
        • Pike V.W.
        • Rash K.S.
        • Chen Z.
        • Pedregal C.
        • Statnick M.A.
        • Kimura Y.
        • et al.
        Synthesis and evaluation of radioligands for imaging brain nociceptin/orphanin FQ peptide (NOP) receptors with positron emission tomography.
        J Med Chem. 2011; 54: 2687-2700
        • Narendran R.
        • Ciccocioppo R.
        • Lopresti B.
        • Paris J.
        • Himes M.L.
        • Mason N.S.
        Nociceptin receptors in alcohol use disorders: A positron emission tomography study using [(11)C]NOP-1A.
        Biol Psychiatry. 2018; 84: 708-714
        • Lohith T.G.
        • Zoghbi S.S.
        • Morse C.L.
        • Araneta M.D.
        • Barth V.N.
        • Goebl N.A.
        • et al.
        Retest imaging of [11C]NOP-1A binding to nociceptin/orphanin FQ peptide (NOP) receptors in the brain of healthy humans.
        Neuroimage. 2014; 87: 89-95
        • Lohith T.G.
        • Zoghbi S.S.
        • Morse C.L.
        • Araneta M.F.
        • Barth V.N.
        • Goebl N.A.
        • et al.
        Brain and whole-body imaging of nociceptin/orphanin FQ peptide receptor in humans using the PET ligand 11C-NOP-1A.
        J Nucl Med. 2012; 53: 385-392
        • Kimura Y.
        • Fujita M.
        • Hong J.
        • Lohith T.G.
        • Gladding R.L.
        • Zoghbi S.S.
        • et al.
        Brain and whole-body imaging in rhesus monkeys of 11C-NOP-1A, a promising PET radioligand for nociceptin/orphanin FQ peptide receptors.
        J Nucl Med. 2011; 52: 1638-1645
        • Kim H.G.
        • Cheon E.J.
        • Bai D.S.
        • Lee Y.H.
        • Koo B.H.
        Stress and heart rate variability: A meta-analysis and review of the literature.
        Psychiatry Investig. 2018; 15: 235-245
        • Shaffer F.
        • Ginsberg J.P.
        An overview of heart rate variability metrics and norms.
        Front Public Health. 2017; 5: 258
        • Pulopulos M.M.
        • Vanderhasselt M.A.
        • De Raedt R.
        Association between changes in heart rate variability during the anticipation of a stressful situation and the stress-induced cortisol response.
        Psychoneuroendocrinology. 2018; 94: 63-71
        • Thayer J.F.
        • Hall M.
        • Sollers 3rd, J.J.
        • Fischer J.E.
        Alcohol use, urinary cortisol, and heart rate variability in apparently healthy men: Evidence for impaired inhibitory control of the HPA axis in heavy drinkers.
        Int J Psychophysiol. 2006; 59: 244-250
        • Tarvainen M.P.
        • Niskanen J.P.
        • Lipponen J.A.
        • Ranta-aho P.O.
        • Karjalainen P.A.
        Kubios HRV—Heart rate variability analysis software.
        Comput Methods Programs Biomed. 2014; 113: 210-220
        • Benjamini Y.
        • Hochberg Y.
        Controlling the false discovery rate: A practical and powerful approach to multiple testing.
        J R Stat Soc Ser B. 1995; 57: 289-300
        • Narendran R.
        • Mason N.S.
        • May M.A.
        • Chen C.M.
        • Kendro S.
        • Ridler K.
        • et al.
        Positron emission tomography imaging of dopamine D2/3 receptors in the human cortex with [11C]FLB 457: Reproducibility studies.
        Synapse. 2011; 65: 35-40
        • Narendran R.
        • Frankle W.G.
        • Mason N.S.
        • Rabiner E.A.
        • Gunn R.
        • Searle G.E.
        • et al.
        Positron emission tomography imaging of amphetamine-induced dopamine release in the human cortex: A comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride.
        Synapse. 2009; 63: 447-461
        • Narendran R.
        • Mason N.S.
        • Laymon C.
        • Lopresti B.
        • Velasquez N.
        • May M.
        • et al.
        A comparative evaluation of the dopamine D2/3 agonist radiotracer [11C]NPA and antagonist [11C]raclopride to measure amphetamine-induced dopamine release in the human striatum.
        J Pharmacol Exp Ther. 2010; 63: 574-584
        • Slifstein M.
        • Laruelle M.
        Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers.
        Nucl Med Biol. 2001; 28: 595-608
        • Spampinato S.
        • Baiula M.
        Agonist-regulated endocytosis and desensitization of the human nociceptin receptor.
        Neuroreport. 2006; 17: 173-177
        • Spampinato S.
        • Baiula M.
        • Calienni M.
        Agonist-regulated internalization and desensitization of the human nociceptin receptor expressed in CHO cells.
        Curr Drug Targets. 2007; 8: 137-146
        • Toll L.
        • Bruchas M.R.
        • Calo G.
        • Cox B.M.
        • Zaveri N.T.
        Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems.
        Pharmacol Rev. 2016; 68: 419-457
        • Corbani M.
        • Gonindard C.
        • Meunier J.C.
        Ligand-regulated internalization of the opioid receptor-like 1: A confocal study.
        Endocrinology. 2004; 145: 2876-2885
        • Mann A.
        • Mouledous L.
        • Froment C.
        • O'Neill P.R.
        • Dasgupta P.
        • Gunther T.
        • et al.
        Agonist-selective NOP receptor phosphorylation correlates in vitro and in vivo and reveals differential post-activation signaling by chemically diverse agonists.
        Sci Signal. 2019; 12eaau8072

      Linked Article

      • The Complex Role of Nociceptin Signaling in Stress: Clarity Through Neuroimaging?
        Biological PsychiatryVol. 87Issue 6
        • Preview
          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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