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Opioids

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Opioids

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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