Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Lowered endogenous mu-opioid receptor availability in subclinical depression and anxiety


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 [11C]carfentanil 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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Opioid receptor distribution.
Fig. 2: Association between depressive and anxious symptoms and MOR.
Fig. 3: Association between BDI-II and STAI-X scores on selected regions of interest.
Fig. 4: Posterior distributions of the regression coefficients for the BDI-II and STAI-X scales.


  1. 1.

    Nummenmaa L, Tuominen LJ. Opioid system and human emotions. Br J Pharmacol. 2018;175:2737–49.

    CAS  PubMed  Google Scholar 

  2. 2.

    van Steenbergen H, Eikemo M, Leknes S. The role of the opioid system in decision making and cognitive control: a review. Cogn Affect Behav Neurosci. 2019;19:435–58.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Lutz PE, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36:195–206.

    CAS  PubMed  Google Scholar 

  4. 4.

    Moffitt TE, Harrington H, Caspi A, Kim-Cohen J, Goldberg D, Gregory AM, et al. Depression and generalized anxiety disorder: cumulative and sequential comorbidity in a birth cohort followed prospectively to age 32 years. Arch Gen Psychiatry. 2007;64:651–60.

    PubMed  Google Scholar 

  5. 5.

    Davis M. Morphine and naloxone: effects on conditioned fear as measured with the potentiated startle paradigm. Eur J Pharmacol. 1979;54:341–7.

    CAS  PubMed  Google Scholar 

  6. 6.

    Good AJ, Westbrook RF. Effects of a microinjection of morphine into the amygdala on the acquisition and expression of conditioned fear and hypoalgesia in rats. Behav Neurosci. 1995;109:631–41.

    CAS  PubMed  Google Scholar 

  7. 7.

    Zarrindast M-R, Babapoor-Farrokhran S, Babapoor-Farrokhran S, Rezayof A. Involvement of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala in anxiety-related behavior. Life Sci. 2008;82:1175–81.

    CAS  PubMed  Google Scholar 

  8. 8.

    Henriksen G, Willoch F. Imaging of opioid receptors in the central nervous system. Brain. 2008;131:1171–96.

    PubMed  Google Scholar 

  9. 9.

    Falcon E, Browne CA, Leon RM, Fleites VC, Sweeney R, Kirby LG, et al. Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology. 2016;41:2344–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Robinson SA, Erickson RL, Browne CA, Lucki I. A role for the mu opioid receptor in the antidepressant effects of buprenorphine. Behav Brain Res. 2016;319:96–103.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15:49–57.

    CAS  PubMed  Google Scholar 

  12. 12.

    Nyhuis PW, Gastpar M, Scherbaum N. Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy. J Clin Psychopharmacol. 2008;28:593–5.

    PubMed  Google Scholar 

  13. 13.

    Emrich HM, Vogt P, Herz A. Possible antidepressive effects of opioids: action of buprenorphine. Ann N Y Acad Sci. 1982;398:108–12.

    CAS  PubMed  Google Scholar 

  14. 14.

    Yovell Y, Bar G, Mashiah M, Baruch Y, Briskman I, Asherov J, et al. Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled. Trial Am J Psychiat. 2015;173:491–8.

    PubMed  Google Scholar 

  15. 15.

    Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL. Morphine use after combat injury in iraq and post-traumatic stress disorder. N Engl J Med. 2010;362:110–7.

    CAS  PubMed  Google Scholar 

  16. 16.

    Bryant RA, Creamer M, O’Donnell M, Silove D, McFarlane AC. A study of the protective function of acute morphine administration on subsequent posttraumatic stress disorder. Biol Psychiatry. 2009;65:438–40.

    CAS  PubMed  Google Scholar 

  17. 17.

    Saxe G, Stoddard F, Courtney D, Cunningham K, Chawla N, Sheridan R, et al. Relationship between acute morphine and the course of PTSD in children with burns. J Am Acad Child Adolesc Psychiatry. 2001;40:915–21.

    CAS  PubMed  Google Scholar 

  18. 18.

    Zubieta JK, Ketter TA, Bueller JA, Xu YJ, Kilbourn MR, Young EA, et al. Regulation of human affective responses by anterior cingulate and limbic mu-opioid neurotransmission. Arch Gen Psychiatry. 2003;60:1145–53.

    CAS  PubMed  Google Scholar 

  19. 19.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Kennedy SE, Koeppe RA, Young EA, Zubieta JK. Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Arch Gen Psychiatry. 2006;63:1199–208.

    CAS  PubMed  Google Scholar 

  21. 21.

    Hsu DT, Sanford BJ, Meyers KK, Love TM, Hazlett KE, Walker SJ, et al. It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder. Mol Psychiatry. 2015;20:193–200.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Tuominen L, Salo J, Hirvonen J, Nagren K, Laine P, Melartin T, et al. Temperament trait Harm Avoidance associates with mu-opioid receptor availability in frontal cortex: A PET study using C-11 carfentanil. Neuroimage. 2012;61:670–6.

    CAS  PubMed  Google Scholar 

  23. 23.

    Liberzon I, Taylor SF, Phan KL, Britton JC, Fig LM, Bueller JA, et al. Altered central micro-opioid receptor binding after psychological trauma. Biol Psychiatry. 2007;61:1030–8.

    CAS  PubMed  Google Scholar 

  24. 24.

    Gross-Isseroff R, Dillon KA, Israeli M, Biegon A. Regionally selective increases in mu opioid receptor density in the brains of suicide victims. Brain Res. 1990;530:312–6.

    CAS  PubMed  Google Scholar 

  25. 25.

    Gabilondo AM, Meana JJ, García-Sevilla JA. Increased density of mu-opioid receptors in the postmortem brain of suicide victims. Brain Res. 1995;682:245–50.

    CAS  PubMed  Google Scholar 

  26. 26.

    Scarr E, Money TT, Pavey G, Neo J, Dean B. Mu opioid receptor availability in people with psychiatric disorders who died by suicide: a case control study. BMC Psychiatry. 2012;12:126.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Zalsman G, Molcho A, Huang Y, Dwork A, Li S, Mann JJ. Postmortem mu-opioid receptor binding in suicide victims and controls. J Neural Transm. 2005;112:949–54.

    CAS  PubMed  Google Scholar 

  28. 28.

    Karsten J, Hartman CA, Smit JH, Zitman FG, Beekman ATF, Cuijpers P, et al. Psychiatric history and subthreshold symptoms as predictors of the occurrence of depressive or anxiety disorder within 2 years. Br J Psychiatry. 2011;198:206–12.

    PubMed  Google Scholar 

  29. 29.

    Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck depression inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77–100.

    Google Scholar 

  30. 30.

    Spielberger CD, Gorsuch RL, Lushene RE. Manual for the state-trait anxiety inventory. Palo Alto, CA: Consulting Psychologists Press; 1970.

    Google Scholar 

  31. 31.

    Frost JJ, Wagner HN Jr., Dannals RF, Ravert HT, Links JM, Wilson AA, et al. Imaging opiate receptors in the human brain by positron tomography. J Comput Assist Tomogr. 1985;9:231–6.

    CAS  PubMed  Google Scholar 

  32. 32.

    Karjalainen T, Tuominen L, Manninen S, Kalliokoski K, Nuutila P, Jääskeläinen IP, et al. Behavioural activation system sensitivity is associated with cerebral μ-opioid receptor availability. Soc Cogn Affect Neurosci. 2016;11:1310–6.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Nummenmaa L, Manninen S, Tuominen L, Hirvonen J, Kalliokoski KK, Nuutila P, et al. Adult attachment style Is associated with cerebral μ-opioid receptor availability in humans. Hum Brain Mapp. 2015;36:3621–8.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Karjalainen T, Santavirta S, Kantonen T, Tuisku J, Tuominen L, Hirvonen J, et al. Magia: robust automated modeling and image processing toolbox for PET neuroinformatics. Front Neuroinform. 2020:604835.

  35. 35.

    Kantonen T, Karjalainen T, Isojärvi J, Nuutila P, Tuisku J, Rinne J, et al. Interindividual variability and lateralization of µ-opioid receptors in the human brain. Neuroimage. 2020;217:116922.

    CAS  PubMed  Google Scholar 

  36. 36.

    Innis RB, Cunningham VJ, Delforge J, Fujita M, Giedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27:1533–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001;293:311–5.

    CAS  PubMed  Google Scholar 

  38. 38.

    Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ. Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. NeuroImage. 1997;6:279–87.

    CAS  PubMed  Google Scholar 

  39. 39.

    Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. NeuroImage. 1996;4:153–8.

    CAS  PubMed  Google Scholar 

  40. 40.

    Frost JJ, Douglass KH, Mayberg HS, Dannals RF, Links JM, Wilson AA. Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography. J Cereb Blood Flow Metab. 1989;9:398–409.

    CAS  PubMed  Google Scholar 

  41. 41.

    Goodkind M, Eickhoff SB, Oathes DJ, Jiang Y, Chang A, Jones-Hagata LB, et al. Identification of a common neurobiological substrate for mental illness. JAMA Psychiatry. 2015;72:305–15.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Hayakawa YK, Sasaki H, Takao H, Mori H, Hayashi N, Kunimatsu A, et al. Structural brain abnormalities in women with subclinical depression, as revealed by voxel-based morphometry and diffusion tensor imaging. J Affect Disord. 2013;144:263–8.

    PubMed  Google Scholar 

  43. 43.

    Kraus C, Hahn A, Savli M, Kranz GS, Baldinger P, Hoeflich A, et al. Serotonin-1A receptor binding is positively associated with gray matter volume—a multimodal neuroimaging study combining PET and structural MRI. Neuroimage. 2012;63:1091–8.

    CAS  PubMed  Google Scholar 

  44. 44.

    Woodward ND, Zald DH, Ding Z, Riccardi P, Ansari MS, Baldwin RM, et al. Cerebral morphology and dopamine D2/D3 receptor distribution in humans: a combined [18F]fallypride and voxel-based morphometry study. Neuroimage. 2009;46:31–8.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Manninen S, Karjalainen T, Tuominen LJ, Hietala J, Kaasinen V, Joutsa J, et al. Cerebral grey matter density is associated with neuroreceptor and neurotransporter availability: a combined PET and MRI study. 2020.

  46. 46.

    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.

    CAS  PubMed  Google Scholar 

  47. 47.

    Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, et al. A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage. 2005;25:1325–35.

    PubMed  Google Scholar 

  48. 48.

    Bürkner P-C. brms: an R package for Bayesian multilevel models using Stan. J Stat Softw. 2017;80:1–28.

    Google Scholar 

  49. 49.

    Gelman A, Carlin JB, Stern HS, Dunson DB, Vehtari A, Rubin DB. Bayesian data analysis. Chapman and Hall/CRC; Boca Raton, FL, 2013.

  50. 50.

    Gabry J, Simpson D, Vehtari A, Betancourt M, Gelman A. Visualization in Bayesian workflow. J R Stat Soc Ser A. 2019;182:389–402.

    Google Scholar 

  51. 51.

    Gelman A, Hill J. Data analysis using regression and multilevel/hierarchical models. Cambridge University Press; New York, NY, 2006.

  52. 52.

    Tuominen L, Nummenmaa L, Keltikangas-Järvinen L, Raitakari O, Hietala J. Mapping neurotransmitter networks with PET: an example on serotonin and opioid systems. Hum Brain Mapp. 2014;35:1875–84.

    PubMed  Google Scholar 

  53. 53.

    Su L, Cai Y, Xu Y, Dutt A, Shi S, Bramon E. Cerebral metabolism in major depressive disorder: a voxel-based meta-analysis of positron emission tomography studies. BMC Psychiatry. 2014;14:321.

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002;3:655.

    CAS  PubMed  Google Scholar 

  55. 55.

    Hamilton JP, Etkin A, Furman DJ, Lemus MG, Johnson RF, Gotlib IH. Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of baseline activation and neural response. Data Am J Psychiatry. 2012;169:693–703.

    PubMed  Google Scholar 

  56. 56.

    Zubieta JK, Dannals RF, Frost JJ. Gender and age influences on human brain mu-opioid receptor binding measured by PET. Am J Psychiatry. 1999;156:842–8.

    CAS  PubMed  Google Scholar 

  57. 57.

    Grisel JE, Bartels JL, Allen SA, Turgeon VL. Influence of beta-Endorphin on anxious behavior in mice: interaction with EtOH. Psychopharmacology. 2008;200:105–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Wand GS, Mangold D, El Deiry S, McCaul ME, Hoover D. Family history of alcoholism and hypothalamic opioidergic activity. Arch Gen Psychiatry. 1998;55:1114–9.

    CAS  PubMed  Google Scholar 

  59. 59.

    Hnasko TS, Sotak BN, Palmiter RD. Morphine reward in dopamine-deficient mice. Nature. 2005;438:854–7.

    CAS  PubMed  Google Scholar 

  60. 60.

    Fox ME, Lobo MK. The molecular and cellular mechanisms of depression: a focus on reward circuitry. Mol Psychiatry 2019;24:1798–815.

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Manninen S, Tuominen L, Dunbar RIM, Karjalainen T, Hirvonen J, Arponen E, et al. Social laughter triggers endogenous opioid release in humans. J Neurosci. 2017;37:6125–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Tuulari JJ, Tuominen L, de Boer FE, Hirvonen J, Helin S, Nuutila P, et al. Feeding releases endogenous opioids in humans. J Neurosci. 2017;37:8284–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Burghardt PR, Rothberg AE, Dykhuis KE, Burant CF, Zubieta JK. Endogenous opioid mechanisms are implicated in obesity and weight loss in humans. J Clin Endocrinol Metab. 2015;100:3193–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Saanijoki T, Tuominen L, Tuulari JJ, Nummenmaa L, Arponen E, Kalliokoski K, et al. Opioid release after high-intensity interval training in healthy human subjects. Neuropsychopharmacology. 2017;43:246–54.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Nummenmaa L, Tuominen L, Dunbar R, Hirvonen J, Manninen S, Arponen E, et al. Social touch modulates endogenous µ-opioid system activity in humans. Neuroimage. 2016;138:242–7.

    CAS  PubMed  Google Scholar 

  66. 66.

    Herman BH, Panksepp J. Effects of morphine and naloxone on separation distress and approach attachment: Evidence for opiate mediation of social affect. Pharmacol Biochem Behav. 1978;9:213–20.

    CAS  PubMed  Google Scholar 

  67. 67.

    Karjalainen T, Seppala K, Glerean E, Karlsson HK, Lahnakoski JM, Nuutila P, et al. Opioidergic regulation of emotional arousal: a combined PET-fMRI study. Cereb Cortex. 2019;29:4006–16.

    PubMed  Google Scholar 

  68. 68.

    Karjalainen T, Karlsson HK, Lahnakoski JM, Glerean E, Nuutila P, Jaaskelainen IP, et al. Dissociable roles of cerebral mu-opioid and type 2 dopamine receptors in vicarious pain: a combined PET-fMRI study. Cereb Cortex. 2017;27:1–10.

    Google Scholar 

  69. 69.

    Heiskanen T, Leppä M, Suvilehto J, Akural E, Larinkoski T, Jääskeläinen IP, et al. The opioid agonist remifentanil increases subjective pleasure during emotional stimulation. Br J Anaesthesiol. 2019;122:E216–E219.

    CAS  Google Scholar 

  70. 70.

    Davis MA, Lin LA, Liu H, Sites BD. Prescription opioid use among adults with mental health disorders in the United States. J Am Board Fam Med. 2017;30:407.

    PubMed  Google Scholar 

  71. 71.

    Peciña M, Karp JF, Mathew S, Todtenkopf MS, Ehrich EW, Zubieta J-K. Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Mol Psychiatry 2019;24:576–87.

    PubMed  Google Scholar 

  72. 72.

    Weerts EM, McCaul ME, Kuwabara H, Yang XJ, Xu XQ, Dannals RF, et al. Influence of OPRM1 Asn(40)Asp variant (A118G) on C-11 carfentanil binding potential: preliminary findings in human subjects. Int J Neuropsychopharmacol. 2013;16:47–53.

    CAS  PubMed  Google Scholar 

Download references

Author information




Acquired the data: TK, VK, JJ, PN, KK, JH, and JR. Analyzed the data: LN, ToK, JI, TK, and JT. Designed the study: LN, ToK, and JR. Wrote the paper: all authors.

Corresponding author

Correspondence to Lauri Nummenmaa.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nummenmaa, L., Karjalainen, T., Isojärvi, J. et al. Lowered endogenous mu-opioid receptor availability in subclinical depression and anxiety. Neuropsychopharmacol. 45, 1953–1959 (2020).

Download citation

Further reading


Quick links