Bluebrain Clusterheadache theory. If we ask any Cluster headache (CH) patient to characterize it, his first words will be EXTREME PAIN (kip scale 8-10), around the eye and surrounding area (forehead for the most) of the affected side of the head. My theory is based on an old theory (from the sixties) and on a different version but very much like the theory you can read in clusterbusters called Neurovascular headache and its treatment Hallucinogenic treatment of the ...(I prefer to call it subhallucinogenic). There are two structures involved in this type of headache, the ophthalmic artery branches and the trigeminal nerve specially those branches that run along with the branches of the opht. artery, intracraneal as well as extracraneal. No matter if it is chronic or episodic every CH has two distinctive phases.
1) NEUROLOGICAL, this phase has to do with the abnormal or absence of serotonin release at the presynaptic button, this reaction should happen as an answer to a vasodilatation stimuli (e.g. red wine). Serotonin has a vasoconstriction effect on the extracerebral intracraneal vessels through the 5HT 1B receptors. It seems that this abnormality is local, as if there is a local regulatory system that controls the tone of the artery (based on serotonin), this could explain why this headache is hemi lateral. I know that it has been mentioned that there is a sudden increase of serotonin metabolites in the urine during a CH seizure contrary to my postulate, I could agree that this happens at the very beginning of a CH seizure, all serotonin is released at one time, but there is no refill of the presynaptic vesicles resulting in less or none presence of serotonin and no vasoconstriction. Already there is a question that arises from this statement, why not give an extra dose of serotonin? Sorry but serotonin doesn't cross the brain blood barrier, then what about an extra dose of tryptophan, unfortunately this could end in a serotonin shock. That's why we need a local serotonin substitute that should activate the local 5HT 1B receptors producing a vasoconstriction of the mentioned artery. This phase is painless.
2) VASCULAR, is as mentioned serotonin dependent. This phase depending on how fast it evolves can be divided in two subtypes;
a) If the dilation of the blood vessel occurs more or less slowly (from one to forty minutes in my case), there will be painless symptoms or at the most slight pain (kip scale 4). This phase is called by some SILENT CH, PRODROMES or just PAINLESS phase. Not everybody experiences this phase. Best medicine at this stage is a 5HT 1B AGONIST or a serotonin like compound. Its a kind of warning, a clusterheadache is evolving and if not treated you will experience the extreme pain and symptoms as b).
b) The vasodiltation occurs suddenly and violently, EXTREMELY PAINFUL, almost all of the symptoms that characterize a CH are present. The trigeminal nerve fibers are activated mechanically by the extreme dilated artery running beside the nerve, at the same time and because of this activation there is a release of substance P and calcitonin-gene-related peptide (CGRP) from the nerve. The release of CGRP leads to even more dilation of these blood vessels and an activation of the pain-transmitting neurons.
As far as we know, the use of a 5HT 1D/1F agonist will disrupt these signals. So what kind of medicine are we looking for? No doubt that the ideal will be some that could regulate the release and refill of serotonin "locally" (we mustn't forget that serotonin has different effects in different parts of your body). The second best would be one that was 5HT 1B and 5HT 1D/1F receptor agonist. The majority of the medicine used today are 5HT 1B/1D/1F receptor agonist (e.g. sumatriptan and other triptans and ergotamine) but and this is a big but, they have some serious side-effects due to the presence of almost the same receptors in other organs and blood vessels than in the brain. Another unfortunate effect is that you can't use them (the majority) as preventative , only as abortives, due to its toxicity or due to its short half-life.
I cannot say for certain but if you neutralize the extreme vasodilatation you will stop the pain. Thats why psilocybin/psilocin-based drugs are the most promising for us patients, because they replace the missing serotonin locally by what I call the two stage process, first stage is the affinity of psilocybin to 5HT2A receptors and then, because of MAO psilocybin becomes psilocin which will replace the missing serotonin by reuptake at the presynaptic button. If you compare serotonin with psilocin, you will see a similarity between these compounds (LSD, LSA, sumatriptans are less similar to serotonin )
This was extensive story, but maybe helpful. Best regards Arild Ejsing.
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