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
1.1. Kappa opioid receptors (KOR / OP2)¶
Acute stress
- Increases dynorphin in ventral tegmental area (VTA) dopamine neurons
- This causes prolonged activation of the kappa opioid receptors (KOR, OP2) in the ventral tegmentum in GABAergic cells
- This in turn causes suppression of long-term potentiation of GABAergic cells (also due to one-time stress)
- 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.
Early childhood stress from social isolation enhances KOR-induced downregulation of nucleus accumbens dopaminergic cells.
The availability of KOR in a network circuit of amygdala, anterior cingulate cortex, and ventral striatum appears to moderate dysphoric/anhedonic symptoms after trauma.
This suggests a mechanism modulated by KOR as a result of chronic stress that correlates with depressive symptoms.
Namalfene (a partial KOR agonist and MOR and δ-opioid receptor antagonist) reduced anticipatory reward behavior in hens but not overall food intake.
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.
Chronic corticosterone administration induces depressive behavior. Simultaneous administration of the (complete) MOR agonist tianeptine remedies this. Tianepin as a serotonin antagonist (thus reducing serotonin) is reported to show at least equivalent antidepressant effects as SSRI, 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..
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.. 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.
Mü opioids modulate stress responses.
Healthy individuals showed increased MOR activation during social rejection of
- Right ventral striatum (nucleus accumbens)
-
Amygdala bilateral
- Thalamus midline
- Periaqueductal gray
Healthy showed during a social acceptance
- Increased MOR activation in:
- Right anterior insula
-
Amygdala left
- A reduced MOR activation in the
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. 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.
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.
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.
NOP receptors are located on dopaminergic nuclei (including the ventral tegmentum. NOP agonism inhibits the neurotransmission of dopamine in the
-
Ventral tegmentum
-
Nucleus accumbens
Chronic stress (social defeats) induces in rats
- Anhedonia
- Increased N/OFQ peptide mRNA levels in the striatum.
NOP and nociceptin receptor mRNA levels in key regions of reward processing and stress regulation
-
Ventral tegmentum
-
Striatum
-
Anterior cingulate cortex
correlate with anhedonia.
Upregulation of NOP appears to influence the development of stress-induced anhedonia.
2. Dynorphins¶
Dynorphins are opioid peptides. Various other forms exist:
- 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.
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. This appears to be facilitated by blockade of the D2 receptor in the nucleus accumbens.
Chronic social stress decreases enkephalin gene expression in the nucleus accumbens of the striatum and opioid receptor expression in the ventral tegmentum.
The expression of D1 and D2 receptors in the rat striatum occurs in different populations through the involvement of proenkephalin and substance P.
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.
In the rostral pole and shell of the nucleus accumbens, proenkephalin cells express only dynorphin and dopamine D1 receptors.
D3 receptors are not expressed by proenkephalin.