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This article deals with endogenous (the body’s own) opioids. Endogenous opioids act as neurotransmitters and are involved in the regulation of stress.

1. Opioid system

The body’s own opioid system is involved in the regulation of

  • Stress
  • Reward processing
  • The emergence of stress-related behaviors such as
    • Anhedonia1
    • Addiction2

1.1. Kappa opioid receptors (KOR / OP2)

Acute stress

  • Increases dynorphin in the dopamine neurons of the VTA3
    • This causes prolonged activation of the kappa-opioid receptors (KOR, OP2) in the ventral tegmentum in GABAergic cells34
    • This in turn causes a suppression of the long-term potentiation of the GABAergic cells (also through one-off stress)3
    • Which in turn reduces dopamine in the nucleus accumbens and triggers anhedonia.
  • Stress or drug abuse increases the activity of the transcription factor CREB (cAMP response element binding protein) in the nucleus accumbens, which increases the expression of the opioid peptide dynorphin, which in turn causes symptoms of anxiety or depression.5

Early childhood stress due to social isolation increases the KOR-induced downregulation of the dopaminergic cells of the nucleus accumbens.6

The availability of KOR in a network circuit consisting of amygdala, anterior cingulate cortex and ventral striatum seems to moderate dysphoric / anhedonic symptoms after trauma.7
This indicates a mechanism modulated by KOR as a result of chronic stress, which correlates with depressive symptoms.1

Namalfene (a partial KOR agonist and MOR and δ-opioid receptor antagonist) reduced anticipatory reward behavior in hens, but not overall food intake.8

KOR antagonists reduced the increased dopamine efflux in vivo in the human DAT gene variant VAL559 and normalized dopamine release. Similarly, the increased DAT-Thr53 phosphorylation and increased DAT trafficking in hDAT VAL559 was normalized. Conversely, wild-type KOR agonists increased DAT-Thr53 phosphorylation and DAT trafficking. hDAT VAL559 is associated with ADHD, ASD and BPD.9

1.2. M-opioid receptors (MOR/μ-opioid receptor/Mü-opioid receptor)

MOR modulate the mesolimbic dopamine pathway and its stress-buffering effect. Mu opioids activate the mesolimbic dopamine pathway via MOR (have a dopamine-increasing effect here) by eliminating the inhibition of GABA interneurons.10

Chronic administration of corticosterone induces depressive behavior. Simultaneous administration of the (complete) MOR agonist tianeptine11 remedies this. Tianeptine as a serotonin antagonist (i.e. one that reduces serotonin) is said to have at least an equivalent antidepressant effect to SSRIs.12 In contrast to SSRI, tianeptine prevented the atrophy of the hippocampal dendrites caused by cortisol and was able to reverse an already occurring dendrite atrophy in the hippocampus, even if the corticosterone supply was continued.13.

Tianeptine causes a number of opiate-like behavioral effects such as analgesia (pain relief), increased motor activity, reduced food intake and altered reward behavior. None of these changes occurred in mice without MOR.11 However, tianeptine did not lead to tolerance development or withdrawal.

The partial mu-opioid agonist buprenorphine reduced the cortisol response and threat perception to the TSST in humans.14

Mü-opioids modulate stress reactions.
During social rejection, healthy individuals showed increased MOR activation of1516

  • Right ventral striatum (nucleus accumbens)
  • Amygdala bilateral
  • Thalamus midline
  • Periaqueductal gray

Healthy people showed during a social acceptance16

  • Increased MOR activation in:
    • Right anterior insula
    • Amygdala left
  • Reduced MOR activation in the
    • Thalamus midline

During rejection, severely depressed individuals showed decreased MOR activation (e.g. decreased endogenous opioid release) in brain regions that regulate stress, mood and motivation, and slower emotional recovery compared to healthy individuals. During social acceptance, only healthy individuals showed increased social motivation, which correlated positively with MOR activation in the nucleus accumbens.15 The authors interpret this as an indication that the response of opioids to acute stress in reward-related regions may be the key to activating a mechanism for actively coping with stressors, which may be impaired in chronic stress and severe depression.

Namalfene (a partial KOR agonist and MOR and δ-opioid receptor antagonist) reduced anticipatory reward behavior in hens, but not overall food intake.8

1.3. Nociceptin/Orphanin FQ (N/OFQ) receptor system

It is possible that the opiopeptide nociceptin/orphanin FQ and its receptors are involved in the development of stress-related anhedonic behaviors.1718
Stress and manipulations that induce depression-like behaviors cause upregulation of the N/OFQ receptor (NOP). A selective N/OFQ receptor antagonist showed a similar antidepressant effect as imipramine and reversed the effects of mild unpredictable stress.19
NOP receptors are located on dopaminergic neurons including the VTA.1 NOP agonism inhibits the neurotransmission of dopamine in the

  • Ventral tegmentum
  • Nucleus accumbens

Chronic stress (social defeat) induced in rats20

  • Anhedonia
  • Increased N/OFQ peptide mRNA levels in the striatum.

NOP and nociceptin receptor mRNA levels in key regions of reward processing and stress regulation1

  • Ventral tegmentum
  • Striatum
  • Anterior cingulate cortex

correlate with anhedonia.

Upregulation of NOP appears to influence the development of stress-induced anhedonia.1

2. Dynorphins

Dynorphins are opioid peptides. There are various other forms:2

  • Dynorphin A
  • Dynorphin B
  • Alpha-Neoendorphin
  • Beta-Neoendorphin
  • Dynorphin A(1-8)
  • Big Dynorphin (a molecule of Dynorphin A and Dynorphin B).

3. Enkephaline

Enkephalins (like endorphins and dynorphins) are opioid peptides produced endogenously (by the body itself).
They are involved in the sensation of pain.

There is met-enkephalin and leu-enkephalin. They are regulated by the proenkephalin gene (PENK).

Enkephalin binds to the opioid receptor, which reduces the sensation of pain.

Stress can regulate the mesocorticolimbic enkephalinergic system. Acute stress increased and chronic stress decreased enkephalin expression in the striatum of rats.2122

Enkephalin regulates the release of mesocorticolimbic dopamine in the ventral tegmentum. Enkephalin mediated the increased release of dopamine in the ventral tegmentum by chronic stress in rats.23 This appears to be facilitated by blockade of the D2 receptor in the nucleus accumbens.24

Chronic social stress reduces enkephalin gene expression in the nucleus accumbens25 and the expression of opioid receptors in the VTA.26

The expression of D1 and D2 receptors in the striatum of the rat occurs in different populations through the involvement of proenkephalin and substance P.27

In the nucleus accumbens as well as in the putamen of the striatum, prodynorphin cells selectively express dopamine D1 receptors, whereas proenkephalin cells selectively express dopamine D2 receptors.28

In the rostral pole and the shell of the nucleus accumbens, proenkephalin cells express only dynorphin and dopamine D1 receptors.28

D3 receptors are not expressed by proenkephalin.28

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  2. Bruchas, Land, Chavkin (2010): The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010 Feb 16;1314:44-55. doi: 10.1016/j.brainres.2009.08.062. PMID: 19716811; PMCID: PMC2819621.

  3. Polter, Barcomb, Chen, Dingess, Graziane, Brown, Kauer (2017): Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress. Elife. 2017 Apr 12;6:e23785. doi: 10.7554/eLife.23785. PMID: 28402252; PMCID: PMC5389861.

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  5. Carlezon, Krystal (2016):Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials. Depress Anxiety. 2016 Oct;33(10):895-906. doi: 10.1002/da.22500. PMID: 27699938; PMCID: PMC5288841.

  6. Karkhanis, Rose, Weiner, Jones (2016): Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System. Neuropsychopharmacology. 2016 Aug;41(9):2263-74. doi: 10.1038/npp.2016.21. PMID: 26860203; PMCID: PMC4946054.

  7. Pietrzak, Naganawa, Huang, Corsi-Travali, Zheng, Stein, Henry, Lim, Ropchan, Lin, Carson, Neumeister (2014): Association of in vivo κ-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology. JAMA Psychiatry. 2014 Nov;71(11):1262-1271. doi: 10.1001/jamapsychiatry.2014.1221. Erratum in: JAMA Psychiatry. 2014 Nov;71(11):1301. PMID: 25229257.

  8. Taylor, Hamlin, Crowley (2020): Anticipatory Behavior for a Mealworm Reward in Laying Hens Is Reduced by Opioid Receptor Antagonism but Not Standard Feed Intake. Front Behav Neurosci. 2020 Jan 14;13:290. doi: 10.3389/fnbeh.2019.00290. PMID: 31992974; PMCID: PMC6971107.

  9. Mayer FP, Stewart A, Varman DR, Moritz AE, Foster JD, Owens AW, Areal LB, Gowrishankar R, Velez M, Wickham K, Phelps H, Katamish R, Rabil M, Jayanthi LD, Vaughan RA, Daws LC, Blakely RD, Ramamoorthy S (2023): Kappa Opioid Receptor Antagonism Rescues Genetic Perturbation of Dopamine Homeostasis: Molecular, Physiological and Behavioral Consequences. bioRxiv [Preprint]. 2023 May 3:2023.05.03.539310. doi: 10.1101/2023.05.03.539310. PMID: 37205452; PMCID: PMC10187322.

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  11. Samuels, Nautiyal, Kruegel, Levinstein, Magalong, Gassaway, Grinnell, Han, Ansonoff, Pintar, Javitch, Sames, Hen (2017): The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor. Neuropsychopharmacology. 2017 Sep;42(10):2052-2063. doi: 10.1038/npp.2017.60. PMID: 28303899; PMCID: PMC5561344.

  12. McEwen, Chattarji, Diamond, Jay, Reagan, Svenningsson, Fuchs (2010): The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Mol Psychiatry. 2010 Mar;15(3):237-49. doi: 10.1038/mp.2009.80. PMID: 19704408; PMCID: PMC2902200.

  13. Magariños, Deslandes, McEwen (1999): Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress. Eur J Pharmacol. 1999 Apr 29;371(2-3):113-22. doi: 10.1016/s0014-2999(99)00163-6. PMID: 10357248.

  14. Bershad, Jaffe, Childs, de Wit (2015) Opioid partial agonist buprenorphine dampens responses to psychosocial stress in humans. Psychoneuroendocrinology. 2015 Feb;52:281-8. doi: 10.1016/j.psyneuen.2014.12.004. PMID: 25544740; PMCID: PMC4297554.

  15. Hsu, Sanford, Meyers, Love, Hazlett, Walker, Mickey, Koeppe, Langenecker, Zubieta (2015): It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder. Mol Psychiatry. 2015 Feb;20(2):193-200. doi: 10.1038/mp.2014.185. PMID: 25600108; PMCID: PMC4469367.

  16. Hsu, Sanford, Meyers, Love, Hazlett, Wang, Ni, Walker, Mickey, Korycinski, Koeppe, Crocker, Langenecker, Zubieta (2013). Response of the μ-opioid system to social rejection and acceptance. Mol Psychiatry. 2013 Nov;18(11):1211-7. doi: 10.1038/mp.2013.96. PMID: 23958960; PMCID: PMC3814222.

  17. Toll, Bruchas, Calo, Cox, Zaveri (2016): Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharmacol Rev. 2016 Apr;68(2):419-57. doi: 10.1124/pr.114.009209. PMID: 26956246; PMCID: PMC4813427.

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  19. Vitale, Ruggieri, Filaferro, Frigeri, Alboni, Tascedda, Brunello, Guerrini, Cifani, Massi (2009): Chronic treatment with the selective NOP receptor antagonist [Nphe 1, Arg 14, Lys 15]N/OFQ-NH 2 (UFP-101) reverses the behavioural and biochemical effects of unpredictable chronic mild stress in rats. Psychopharmacology (Berl). 2009 Dec;207(2):173-89. doi: 10.1007/s00213-009-1646-9. PMID: 19711054.

  20. Der-Avakian, D’Souza, Potter, Chartoff, Carlezon, Pizzagalli, Markou (2017): Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats. Psychopharmacology (Berl). 2017 May;234(9-10):1603-1614. doi: 10.1007/s00213-017-4584-y. PMID: 28280884; PMCID: PMC5420477.

  21. Lucas, Wang, McCall, McEwen (2007): Effects of immobilization stress on neurochemical markers in the motivational system of the male rat. Brain Res. 2007 Jun 25;1155:108-15. doi: 10.1016/j.brainres.2007.04.063. Erratum in: Brain Res. 2007 Dec 12;1184:372. PMID: 17511973; PMCID: PMC2752980. mit weiteren Nachweisen

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  24. Maldonado, Daugé, Feger, Roques (1990): Chronic blockade of D2 but not D1 dopamine receptors facilitates behavioural responses to endogenous enkephalins, protected by kelatorphan, administered in the accumbens in rats. Neuropharmacology. 1990 Mar;29(3):215-23. doi: 10.1016/0028-3908(90)90004-b. PMID: 2157999.

  25. Lucas, Celen, Tamashiro, Blanchard, Blanchard, Markham, Sakai, McEwen (2003):Repeated exposure to social stress has long-term effects on indirect markers of dopaminergic activity in brain regions associated with motivated behavior. Neuroscience. 2004;124(2):449-57. doi: 10.1016/j.neuroscience.2003.12.009. PMID: 14980394.

  26. Nikulina, Miczek, Hammer (2005): Prolonged effects of repeated social defeat stress on mRNA expression and function of mu-opioid receptors in the ventral tegmental area of rats. Neuropsychopharmacology. 2005 Jun;30(6):1096-103. doi: 10.1038/sj.npp.1300658. PMID: 15668724.

  27. Le Moine, Bloch (1995): D1 and D2 dopamine receptor gene expression in the rat striatum: sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAs in distinct neuronal populations of the dorsal and ventral striatum. J Comp Neurol. 1995 May 8;355(3):418-26. doi: 10.1002/cne.903550308. PMID: 7636023.

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