Social status and demographic effects of the kappa opioid receptor: a PET imaging study with a novel agonist radiotracer in healthy volunteers

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Abstract

Kappa opioid receptors (KORs) have been characterized as an aversive system in the brain and implicated in social behavior in preclinical models. This work investigated the effect of social status on the KOR system in humans using positron emission tomography (PET) imaging with the novel KOR agonist radiotracer [11C]EKAP. Eighteen healthy participants (mean age 41.2 ± 9.3) completed the Barratt Simplified Measure of Social Status (BSMSS), an MRI and an [11C]EKAP PET scan on the High Resolution Research Tomograph. Arterial blood sampling and metabolite analysis were conducted to obtain the input function. Regions of interest were based upon an MR template and included the reward/aversion areas of the brain. The multilinear analysis-1 (MA1) method was applied to the regional time-activity curves (TACs) to calculate [11C]EKAP regional volume of distribution (VT). Mixed models and Pearson correlation coefficients were used for body mass index (BMI), gender and age, with age being dropped in subsequent analyses because of nonsignificance. An overall effect of primary ROIs (F7, 112 7.43, p < 0.0001), BSMSS score (F1, 13 7.45, p = 0.02), BMI (F1, 13 23.5, p < 0.001), and gender (F1, 13 23.75, p < 0.001), but not age (F1, 13 1.12, p = 0.35) was observed. Regional [11C]EKAP VT and BSMSS were found to be negatively correlated in the amygdala (r = −0.69, p < 0.01), anterior cingulate cortex (r = −0.56, p = 0.02), caudate (r = −0.66, p < 0.01), frontal cortex (r = −0.52, p = 0.04), hippocampus (r = −0.60, p = 0.01), pallidum (r = −0.59, p = 0.02), putamen (r = −0.62, p = 0.01), and ventral striatum (r = −0.66, p < 0.01). In secondary (non-reward) regions, correlations of [11C]EKAP VT and BSMSS were nonsignificant with the exception of the insula. There was an inverse correlation between social status and KOR levels that was largely specific to the reward/aversion (e.g., saliency) areas of the brain. This finding suggests the KOR system may act as a mediator for the negative effects of social behaviors in humans.

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References

  1. 1.

    Minami M, Satoh M. Molecular biology of the opioid receptors: structures, functions and distributions. Neurosci Res. 1995;23:121–45.

  2. 2.

    Mansour A, Fox CA, Thompson RC, Akil H, Watson SJ. Mu-Opioid receptor mRNA expression in the rat CNS: comparison to mu-receptor binding. Brain Res. 1994;643:245–65.

  3. 3.

    Simonin F, Gaveriaux-Ruff C, Befort K, Matthes H, Lannes B, Micheletti G, et al. Kappa-opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci USA. 1995;92:7006–10.

  4. 4.

    Helal MA, Habib ES, Chittiboyina AG. Selective kappa opioid antagonists for treatment of addiction, are we there yet? Eur J Med Chem. 2017;141:632–47.

  5. 5.

    Akil H, Owens C, Gutstein H, Taylor L, Curran E, Watson S. Endogenous opioids: overview and current issues. Drug Alcohol Depend. 1998;51:127–40.

  6. 6.

    Koob GF, Mason BJ. Existing and future drugs for the treatment of the dark side of addiction. Annu Rev Pharmacol Toxicol. 2016;56:299–322.

  7. 7.

    Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci. 2005;8:1442–4.

  8. 8.

    Wee S, Koob GF. The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology (Berl). 2010;210:121–35.

  9. 9.

    Di Chiara G, Imperato A. Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther. 1988;244:1067–80.

  10. 10.

    Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010;1314:44–55.

  11. 11.

    Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C. The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J Neurosci. 2008;28:407–14.

  12. 12.

    Karkhanis AN, Rose JH, Weiner JL, Jones SR. Early-life social isolation stress increases kappa opioid receptor responsiveness and downregulates the dopamine system. Neuropsychopharmacology. 2016;41:2263–74.

  13. 13.

    Nabeshima T, Kamei H, Matsuno K, Kameyama T. Conditioned suppression and opioid kappa receptor in mice. J Pharmacobiodyn. 1986;9:74–80.

  14. 14.

    Koob GF. The dark side of emotion: the addiction perspective. Eur J Pharmacol. 2015;753:73–87.

  15. 15.

    Chavkin C, Shoemaker WJ, McGinty JF, Bayon A, Bloom FE. Characterization of the prodynorphin and proenkephalin neuropeptide systems in rat hippocampus. J Neurosci. 1985;5:808–16.

  16. 16.

    Koob GF, Le Moal M. Addiction and the brain antireward system. Annu Rev Psychol. 2008;59:29–53.

  17. 17.

    Lalanne L, Ayranci G, Kieffer BL, Lutz PE. The kappa opioid receptor: from addiction to depression, and back. Front Psychiatry. 2014;5:170.

  18. 18.

    Lutz PE, Gross JA, Dhir SK, Maussion G, Yang J, Bramoulle A, et al. Epigenetic regulation of the kappa opioid receptor by child abuse. Biol Psychiatry 2017, 84:751–61.

  19. 19.

    Vanderschuren LJ, Niesink RJ, Spruijt BM, Van Ree JM. Mu- and kappa-opioid receptor-mediated opioid effects on social play in juvenile rats. Eur J Pharmacol. 1995;276:257–66.

  20. 20.

    Robles CF, McMackin MZ, Campi KL, Doig IE, Takahashi EY, Pride MC, et al. Effects of kappa opioid receptors on conditioned place aversion and social interaction in males and females. Behav Brain Res. 2014;262:84–93.

  21. 21.

    McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C. Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system. Neuropsychopharmacology. 2006;31:1241–8.

  22. 22.

    Resendez SL, Kuhnmuench M, Krzywosinski T, Aragona BJ. Kappa-opioid receptors within the nucleus accumbens shell mediate pair bond maintenance. J Neurosci. 2012;32:6771–84.

  23. 23.

    Riters LV, Cordes MA, Stevenson SA. Prodynorphin and kappa opioid receptor mRNA expression in the brain relates to social status and behavior in male European starlings. Behav Brain Res. 2017;320:37–47.

  24. 24.

    Berube P, Laforest S, Bhatnagar S, Drolet G. Enkephalin and dynorphin mRNA expression are associated with resilience or vulnerability to chronic social defeat stress. Physiol Behav. 2013;122:237–45.

  25. 25.

    Donahue RJ, Landino SM, Golden SA, Carroll FI, Russo SJ, Carlezon WA Jr. Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system. Behav Pharmacol. 2015;26:654–63.

  26. 26.

    Nocjar C, Zhang J, Feng P, Panksepp J. The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus. Neuroscience. 2012;218:138–53.

  27. 27.

    Li S, Zheng MQ, Naganawa M, Kim S, Gao H, Kapinos M, et al. Development and in vivo evaluation of a novel kappa opioid receptor agonist as PET radiotracer with superior imaging characteristics. J Nucl Med. 2019.

  28. 28.

    Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33.

  29. 29.

    American Psychiatric Association., American Psychiatric Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th ed. Washington, DC: American Psychiatric Association; 2000.

  30. 30.

    Barratt W. The Barratt Simplified Measure of Social Status (BSMSS) measuring SES. 2006. Available from: https://www.wbarratt.indstate.edu/socialclass/Barratt Simplifed Measure of Social Status.pdf

  31. 31.

    Matuskey D, Gaiser EC, Gallezot JD, Angarita GA, Pittman B, Nabulsi N, et al. A preliminary study of dopamine D2/3 receptor availability and social status in healthy and cocaine dependent humans imaged with [(11)C](+)PHNO. Drug Alcohol Depend. 2015;154:167–73.

  32. 32.

    Martinez D, Orlowska D, Narendran R, Slifstein M, Liu F, Kumar D, et al. Dopamine type 2/3 receptor availability in the striatum and social status in human volunteers. Biol Psychiatry. 2010;67:275–8.

  33. 33.

    Hollingshead AB. Four factor index of social status. New Haven, CT: Department of Sociology, Yale University; 1975.

  34. 34.

    Li SZM, Lin SF, Kim SJ, Naganawa M, Carson R, Huang, Y, et al. Development and in vivo evaluation of a novel kappa opioid receptor agonist as PET radiotracer with superior imaging characteristics. J Nucl Med. 2014;1112:s55.

  35. 35.

    Naganawa M, Jacobsen LK, Zheng MQ, Lin SF, Banerjee A, Byon W, et al. Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptor in humans: kinetic model selection, test-retest reproducibility and receptor occupancy by the antagonist PF-04455242. Neuroimage. 2014;99:69–79.

  36. 36.

    Carson RE, Barker, WC, Liow, J-S, Johnson, CA. Design of a motioncompensation OSEM list-mode algorithm for resolution-recovery reconstruction of the HRRT. In: Conference Record, IEEE Nuclear Science Symposium and Medical Imaging Conference, Portland, OR. pp. 3281–5; 2003.

  37. 37.

    Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002;15:273–89.

  38. 38.

    Matuskey D, Gallezot JD, Pittman B, Williams W, Wanyiri J, Gaiser E, et al. Dopamine D(3) receptor alterations in cocaine-dependent humans imaged with [(1)(1)C](+)PHNO. Drug Alcohol Depend. 2014;139:100–5.

  39. 39.

    Vijay A, Wang S, Worhunsky P, Zheng MQ, Nabulsi N, Ropchan J, et al. PET imaging reveals sex differences in kappa opioid receptor availability in humans, in vivo. Am J Nucl Med Mol Imaging. 2016;6:205–14.

  40. 40.

    Ragen BJ, Maninger N, Mendoza SP, Bales KL. The effects of morphine, naloxone, and kappa opioid manipulation on endocrine functioning and social behavior in monogamous titi monkeys (Callicebus cupreus). Neuroscience. 2015;287:32–42.

  41. 41.

    Ragen BJ, Freeman SM, Laredo SA, Mendoza SP, Bales KL. Mu and kappa opioid receptor distribution in the monogamous titi monkey (Callicebus cupreus): implications for social behavior and endocrine functioning. Neuroscience. 2015;290:421–34.

  42. 42.

    Martin TJ, Sexton T, Kim SA, Severino AL, Peters CM, Young LJ, et al. Regional differences in mu and kappa opioid receptor G-protein activation in brain in male and female prairie voles. Neuroscience. 2015;311:422–9.

  43. 43.

    Bershad AK, Jaffe JH, Childs E, de Wit H. Opioid partial agonist buprenorphine dampens responses to psychosocial stress in humans. Psychoneuroendocrinology. 2015;52:281–8.

  44. 44.

    Wardle MC, Bershad AK, de Wit H. Naltrexone alters the processing of social and emotional stimuli in healthy adults. Soc Neurosci. 2016;11:579–91.

  45. 45.

    Pietrzak RH, Naganawa M, Huang Y, Corsi-Travali S, Zheng MQ, Stein MB, et al. Association of in vivo kappa-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology. JAMA Psychiatry. 2014;71:1262–70.

  46. 46.

    Wiers CE, Shokri-Kojori E, Cabrera E, Cunningham S, Wong C, Tomasi D, et al. Socioeconomic status is associated with striatal dopamine D2/D3 receptors in healthy volunteers but not in cocaine abusers. Neurosci Lett. 2016;617:27–31.

  47. 47.

    Worhunsky PD, Matuskey D, Gallezot JD, Gaiser EC, Nabulsi N, Angarita GA, et al. Regional and source-based patterns of [(11)C]-(+)-PHNO binding potential reveal concurrent alterations in dopamine D2 and D3 receptor availability in cocaine-use disorder. Neuroimage. 2017;148:343–51.

  48. 48.

    Gaiser EC, Gallezot JD, Worhunsky PD, Jastreboff AM, Pittman B, Kantrovitz L, et al. Elevated dopamine D2/3 receptor availability in obese individuals: a PET imaging study with [(11)C](+)PHNO. Neuropsychopharmacology. 2016;41:3042–50.

  49. 49.

    Caravaggio F, Ku Chung J, Plitman E, Boileau I, Gerretsen P, Kim J, et al. The relationship between subcortical brain volume and striatal dopamine D2/3 receptor availability in healthy humans assessed with [(11) C]-raclopride and [(11) C]-(+)-PHNO PET. Hum Brain Mapp. 2017;38:5519–34.

  50. 50.

    Morgan D, Grant KA, Gage HD, Mach RH, Kaplan JR, Prioleau O, et al. Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci. 2002;5:169–74.

  51. 51.

    Yamaguchi Y, Lee YA, Kato A, Jas E, Goto Y. The roles of dopamine D2 receptor in the social hierarchy of rodents and primates. Sci Rep. 2017;7:43348.

  52. 52.

    Werling LL, Frattali A, Portoghese PS, Takemori AE, Cox BM. Kappa receptor regulation of dopamine release from striatum and cortex of rats and guinea pigs. J Pharmacol Exp Ther. 1988;246:282–6.

  53. 53.

    Svingos AL, Chavkin C, Colago EE, Pickel VM. Major coexpression of kappa-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles. Synapse. 2001;42:185–92.

  54. 54.

    Ebner SR, Roitman MF, Potter DN, Rachlin AB, Chartoff EH. Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens. Psychopharmacology (Berl). 2010;210:241–52.

  55. 55.

    Way BM, Taylor SE, Eisenberger NI. Variation in the mu-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection. Proc Natl Acad Sci USA. 2009;106:15079–84.

  56. 56.

    Panksepp J, Herman B, Conner R, Bishop P, Scott JP. The biology of social attachments: opiates alleviate separation distress. Biol Psychiatry. 1978;13:607–18.

  57. 57.

    Trezza V, Damsteegt R, Achterberg EJ, Vanderschuren LJ. Nucleus accumbens mu-opioid receptors mediate social reward. J Neurosci. 2011;31:6362–70.

  58. 58.

    Hsu DT, Sanford BJ, Meyers KK, Love TM, Hazlett KE, Wang H, et al. Response of the mu-opioid system to social rejection and acceptance. Mol Psychiatry. 2013;18:1211–7.

  59. 59.

    Panksepp J, Herman BH, Vilberg T, Bishop P, DeEskinazi FG. Endogenous opioids and social behavior. Neurosci Biobehav Rev. 1980;4:473–87.

  60. 60.

    D’Amato FR, Pavone F. Modulation of nociception by social factors in rodents: contribution of the opioid system. Psychopharmacology (Berl). 2012;224:189–200.

  61. 61.

    Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD. The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain. Pain. 1999;83:339–45.

  62. 62.

    Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD. Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med. 1996;2:1248–50.

  63. 63.

    Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD. Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett. 1996;205:207–9.

  64. 64.

    Karkhanis A, Holleran KM, Jones SR. Dynorphin/kappa opioid receptor signaling in preclinical models of alcohol, drug, and food addiction. Int Rev Neurobiol. 2017;136:53–88.

  65. 65.

    Khawaja XZ, Bailey CJ, Green IC. Central mu, delta, and kappa opioid binding sites, and brain and pituitary beta-endorphin and met-enkephalin in genetically obese (ob/ob) and lean mice. Life Sci. 1989;44:1097–105.

  66. 66.

    Jarosz PA. The effect of kappa opioid receptor antagonism on energy expenditure in the obese Zucker rat. Biol Res Nurs. 2007;8:294–9.

  67. 67.

    Ferguson-Segall M, Flynn JJ, Walker J, Margules DL. Increased immunoreactive dynorphin and leu-enkephalin in posterior pituitary of obese mice (ob/ob) and super-sensitivity to drugs that act at kappa receptors. Life Sci. 1982;31:2233–6.

  68. 68.

    Wolinsky TD, Carr KD, Hiller JM, Simon EJ. Chronic food restriction alters mu and kappa opioid receptor binding in the parabrachial nucleus of the rat: a quantitative autoradiographic study. Brain Res. 1996;706:333–6.

  69. 69.

    Radhakrishnan R, Nabulsi N, Gaiser E, Gallezot JD, Henry S, Planeta B, et al. Age-related change in 5-HT6 receptor availability in healthy male volunteers measured with (11)C-GSK215083 PET. J Nucl Med. 2018.

  70. 70.

    Matuskey D, Pittman B, Planeta-Wilson B, Walderhaug E, Henry S, Gallezot JD, et al. Age effects on serotonin receptor 1B as assessed by PET. J Nucl Med. 2012;53:1411–4.

  71. 71.

    Matuskey D, Worhunksy P, Correa E, Pittman B, Gallezot JD, Nabulsi N, et al. Age-related changes in binding of the D2/3 receptor radioligand [(11)C](+)PHNO in healthy volunteers. Neuroimage. 2016;130:241–7.

  72. 72.

    Moses-Kolko EL, Price JC, Shah N, Berga S, Sereika SM, Fisher PM, et al. Age, sex, and reproductive hormone effects on brain serotonin-1A and serotonin-2A receptor binding in a healthy population. Neuropsychopharmacology. 2011;36:2729–40.

  73. 73.

    Hiller JM, Fan LQ, Simon EJ. Age-related changes in kappa opioid receptors in the guinea-pig brain: a quantitative autoradiographic study. Neuroscience. 1992;50:663–73.

  74. 74.

    Eghlidi DH, Haley GE, Noriega NC, Kohama SG, Urbanski HF. Influence of age and 17beta-estradiol on kisspeptin, neurokinin B, and prodynorphin gene expression in the arcuate-median eminence of female rhesus macaques. Endocrinology. 2010;151:3783–94.

  75. 75.

    Carlezon WA Jr., Krystal AD. Kappa-opioid antagonists for psychiatric disorders: from bench to clinical trials. Depress Anxiety. 2016;33:895–906.

  76. 76.

    Crowley NA, Kash TL. Kappa opioid receptor signaling in the brain: circuitry and implications for treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2015;62:51–60.

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Matuskey, D., Dias, M., Naganawa, M. et al. Social status and demographic effects of the kappa opioid receptor: a PET imaging study with a novel agonist radiotracer in healthy volunteers. Neuropsychopharmacol. 44, 1714–1719 (2019) doi:10.1038/s41386-019-0379-7

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