Endorphins and opioid pathways
Neuro peptides and opiate receptors
Role in addiction
The endorphin system and the role it plays in the brain is one of the more complex and newer frontiers in neuroscience. This post is a short introduction to some of the basic information I have found and how it pertains to the pathophysiology of addiction.
*note: the war to stamp out opium does not seem to be going well.
The known use of the latex obtained from the seed pod of Papaver Somniferum, the opium poppy, for both medicinal and non medicinal purposes is as old as recorded history. More recently the refined extracts, morphine, codeine, semisynthetic heroin, hydrocodone and other opiate derived compounds are used both legally and illegally throughout the world. Raw opium is about 12% morphine. This can then be further refined to produce heroin.
There are both legal and illegal markets for opium, however reliable production statistics are difficult to find.
Methadone and fentanyl are both purely synthetic.
It was not until the 1970s that the neural receptor for morphine was found and shortly after neuropeptides, the endogenously produced opioids were isolated. While many questions remain unanswered the addictive properties of opioids, the function of the endogenous system, and it’s role in alcohol use disorder are beginning to come into focus.
Radiolabeled agents have been developed with specific binding affinity for different opioid receptors. PET images above reflect distribution and concentration of receptor types.
- Mu
- Kappa
- Delta
- Nocioceptin – Orphanin
Note the predominance of Mu receptors in central brain structures such as the Caudate, Amygdala, midbrain, and Striatum, areas important in the reward pathway and other functions. Opiate drugs have strong affinity for Mu receptors.
While opioid receptors are widely distributed in the brain they are produced only in a few select nerve bundles, the hypothalamus and the anterior pituitary. Endorphins are produced in the pituitary in response to Corticotropin releasing factor from the hypothalamus.
This shows the chemical structure of beta-endorphin. Peptides are protein like strings of amino acids with complex three dimensional structures. In that respect and others they differ from small neurotransmitters like dopamine or serotonin.
Shown is a diagram of beta-endorphin and a morphine molecule binding to Mu-receptors. Another difference from neurotransmitters is that these peptides do not have reuptake transporters. They degrade quickly in the body which is a challenge in research.
Peptides like beta-endorphin are cleaved from segments of larger precursors present in the anterior pituitary.
I feel happier already.
There are subtypes of peptides and subtypes of receptors.
The 3 major peptides are:
Enkephalin
Endorphin
Dynorphin
The 3 major receptors are:
Mu
Kappa
Delta
Each peptide preferentially binds to a specific receptor type. There are significant functional overlaps and differences in effect of agents, receptors, and locations.
All three major receptors are involved with analgesia.
The key takeaway points are:
Opiate drugs like morphine primarily bind to Mu receptors as does b-endorphin. They are very effective pain relievers. They also sedate which can be useful. They produce euphoria and respiratory depression. Euphoria can lead to addiction. Respiratory depression can lead to death from overdose.
Naloxone is a strong Mu receptor antagonist. It reverses opioid effects completely.
Naltrexone is a weak Mu receptor antagonist. It is used in addiction treatment.
Kappa receptors bind dynorphins and produce both analgesia and dysphoria. So that isn’t good either.
Written in 2006. The holy grail has yet to be discovered.
How do opioids work?
In general opioids inhibit nerve conduction. Inhibition of pain signaling accounts for analgesic effects.
This occurs in 3 steps.
Opioid binds to receptor.
- This results in a protein mediated decrease of cAMP (cyclic adenosine mono phosphate) production. cAMP is an essential second messenger for cellular processes including production and release of neurotransmitters.
- Calcium channels close. Ca++ is needed for transmitter release.
- Potassium ion channels release K+ resulting in increased negative charge across the cell membrane. It makes it harder for the cell to initiate an action potential. The cell is now hyperpolarized.
The opiate system is an active area of investigation and is thought to play a role in alcohol use disorder in addition to opiate addiction.
The hypothesis is that endorphins are released from the arcuate nucleus in the hypothalamus in response to alcohol. This has been demonstrated in animal models.
Endorphin then blocks GABA inhibitory neurons controlling the Dopamine reward system. This frees up positive firing inputs coming in from glutamine pathways.
The result is release of dopamine and reward activation. This mechanism is incompletely understood currently. It does explain how the partial opiate antagonist Naltrexone helps to prevent relapse in Alcohol Use Disorder.
Opioid tolerance requiring larger doses to achieve the same effect is incompletely understood at this time.
Kappa receptor dynorphin induced dysphoria is thought to further drive the addictive cycle.
When combined with coping skills or supportive therapy Naltrexone is thought to help restore functional dopamine regulation and aid in preventing relapse.
Achieving optimal outcomes for people wanting to overcome substance use is an ongoing effort. There have been some gains with many challenges remaining.
Combined medication and psychosocial treatment and support has been shown to be most effective in several studies, however there is considerable difference between individuals. Guiding treatment providers in treatment options is an ongoing effort and a good subject for additional review.
Breathing has now been scientifically proven to beneficial.
Thank you for your consideration in reviewing this post. Any feedback is welcome.
For educational and informational purposes only. No commercial or institutional interests. This post should not be considered medical or professional advice. Images and data obtained from those freely available on the World Wide Web.
7/2023
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Sober Synthesis 
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