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

1. Opioid System

The endogenous opioid system is involved in the regulation of

  • Stress
  • Reward Processing
  • The development of stress-related behaviors such as
    • Anhedonia1
    • Addiction2

1.1. Kappa opioid receptors (KOR / OP2)

Acute stress

  • Increases dynorphin in ventral tegmental area (VTA) dopamine neurons3
    • This causes prolonged activation of the kappa opioid receptors (KOR, OP2) in the ventral tegmentum in GABAergic cells34
    • This in turn causes suppression of long-term potentiation of GABAergic cells (also due to one-time stress)3
    • Which in turn decreases 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 from social isolation enhances KOR-induced downregulation of nucleus accumbens dopaminergic cells.6

The availability of KOR in a network circuit of amygdala, anterior cingulate cortex, and ventral striatum appears to moderate dysphoric/anhedonic symptoms after trauma.7
This suggests a mechanism modulated by KOR as a result of chronic stress that 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

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 (acting to increase dopamine here) by removing the inhibition of GABA interneurons.9

Chronic corticosterone administration induces depressive behavior. Simultaneous administration of the (complete) MOR agonist tianeptine10 remedies this. Tianepin as a serotonin antagonist (thus reducing serotonin) is reported to show at least equivalent antidepressant effects as SSRI,11 In contrast to SSRI, tianeptine prevented cortisol-induced hippocampal dendrite athropy and was able to reverse hippocampal dendrite athropy that had already occurred, even when corticosterone intake was continued.12.

Tianeptine causes several opiate-like behavioral effects such as analgesia (pain relief), increased motor activity, decreased food intake, and altered reward behavior. All of the above changes did not occur in mice lacking MOR.10. 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.13

Mü opioids modulate stress responses.
Healthy individuals showed increased MOR activation during social rejection of1415

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

Healthy showed during a social acceptance15

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

Severely depressed individuals showed decreased MOR activation (e.g., decreased endogenous opioid release) in brain regions regulating stress, mood, and motivation during rejection and slower emotional recovery compared with healthy individuals. During social acceptance, only healthy individuals showed increased social motivation, which correlated positively with MOR activation in the nucleus accumbens.14 The authors interpret this as evidence that the opioid response to acute stress in reward-related regions may be key to activating a mechanism for actively coping with stressors that may be impaired in chronic stress and major 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-induced anhedonic behaviors.1617
Stress and manipulations that induce depression-like behaviors cause N/OFQ receptor (NOP) upregulation. A selective N/OFQ receptor antagonist showed similar antidepressant effects to imipramine and remediated the consequences of mild unpredictable stress.18
NOP receptors are located on dopaminergic nuclei (including the ventral tegmentum.1 NOP agonism inhibits the neurotransmission of dopamine in the

  • Ventral tegmentum
  • Nucleus accumbens

Chronic stress (social defeats) induces in rats19

  • 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. Various other forms exist: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 endogenously (produced by the body itself) produced opioid peptides.
They are involved in the sensation of pain.

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

Enkephalin binds to the opioid receptor, causing a reduction in pain sensation.

Stress can regulate the mesocorticolimbic enkephalinergic system. Acute stress increased, chronic stress decreased enkephalin expression in the striatum of rats.2021

Enkephalin regulates the release of mesocorticolimbic dopamine in the ventral tegmentum. Enkephalin mediated the increased dopamine release in the ventral tegmentum by chronic stress in rats.22 This appears to be facilitated by blockade of the D2 receptor in the nucleus accumbens.23

Chronic social stress decreases enkephalin gene expression in the nucleus accumbens of the striatum 24 and opioid receptor expression in the ventral tegmentum.25

The expression of D1 and D2 receptors in the rat striatum occurs in different populations through the involvement of proenkephalin and substance P.26

In the nucleus accumbens as in the putamen of the striatum, prodynorphin cells selectively express dopamine D1 receptors, whereas proenkephalin cells selectively express dopamine D2 receptors.27

In the rostral pole and shell of the nucleus accumbens, proenkephalin cells express only dynorphin and dopamine D1 receptors.27

D3 receptors are not expressed by proenkephalin.27

  1. Ironside, Kumar, Kang, Pizzagalli (2018): Brain mechanisms mediating effects of stress on reward sensitivity. Curr Opin Behav Sci. 2018 Aug;22:106-113. doi: 10.1016/j.cobeha.2018.01.016. PMID: 30349872; PMCID: PMC6195323.

  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.

  4. Graziane, Polter, Briand, Pierce, Kauer (2013): Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron. 2013 Mar 6;77(5):942-54. doi: 10.1016/j.neuron.2012.12.034. PMID: 23473323; PMCID: PMC3632376.

  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. Johnson, North (1992): Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci. 1992 Feb;12(2):483-8. doi: 10.1523/JNEUROSCI.12-02-00483.1992. PMID: 1346804; PMCID: PMC6575608.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Gavioli EC, Calo’ G. Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs. Pharmacol Ther. 2013 Oct;140(1):10-25. doi: 10.1016/j.pharmthera.2013.05.008. PMID: 23711793.

  18. 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.

  19. 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.

  20. 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

  21. Lucas, Celen, Tamashiro, Blanchard, Blanchard, Markham, Sakai, McEwen (2004): 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.

  22. Kalivas, Abhold (1987): Enkephalin release into the ventral tegmental area in response to stress: modulation of mesocorticolimbic dopamine. Brain Res. 1987 Jun 30;414(2):339-48. doi: 10.1016/0006-8993(87)90015-1. PMID: 3620936.

  23. 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.

  24. 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.

  25. 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.

  26. 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.

  27. Curran, Watson (1995): Dopamine receptor mRNA expression patterns by opioid peptide cells in the nucleus accumbens of the rat: a double in situ hybridization study. J Comp Neurol. 1995 Oct 9;361(1):57-76. doi: 10.1002/cne.903610106. PMID: 8550882.

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