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Serotonin and migraine

Serotonin and migraineSerotonin and 5-hydroxytryptamine (5-HT) or Enteramin is a tissue hormone and neurotransmitter that is found in the central nervous system, intestinal nervous system, cardiovascular system and blood.

The name of this biogenic amine is derived from its effect on blood pressure.  Serotonin is a component of the serum, which regulates the tone (tension) of blood vessels.  It also affects the gastro-intestinal activity and signal transmission in the central nervous system.

History

The presence of a substance in the blood, the contraction of the blood vessels, was accepted in the mid-19th Century by Carl Ludwig.  Vittorio Erspamer isolated in the 1930s, a substance from the mucosa of the gastrointestinal tract, a contraction of smooth muscle.

He called it “Enteramin”.  In 1948 Maurice Rapport, Arda Green, and Irvine Page named the contracting blood vessels in a substance “serotonin.”   The structure of this substance, which Maurice Rapport postulated, was confirmed in 1951 by synthesis.

Shortly thereafter, Vittorio Erspamer could show that what he found and Enteramin Report’s serotonin are identical.   Irvine Page and Betty Twarog succeeded in 1953 with the detection of serotonin in the brain, another important discovery.

They were responsible for the effect of serotonin receptors studied intensively in the following years.  John Gaddum resulted in a distinctive “D” – and “M” receptors.  But only with the advent of molecular biological methods in the 1990s, did a large number of different serotonin receptors become obvious.
Occurrence

Serotonin is widely distributed in nature. Already single-celled organisms like amoeba can produce serotonin as well as producers of plants and higher fungi.  In the stinging hairs of the nettle serotonin is partly responsible. The serotoninreichsten plant foods include walnuts, which can contain about 300 micrograms / g serotonin.

But bananas, pineapples, kiwis, plums, tomatoes, cocoa and derived products, such as chocolate all contain serotonin in the ppm range. The unusually high serotonin content, especially for walnuts, is specific to explain mechanisms of degradation-combustion of ammonia.  Descendants of serotonin, such as Feruloylserotonin and 4-Cumaroylserotonin, are a function assumed to be phytoalexins.

In the animal kingdom Serotonin is found in almost all the representatives.  It is one of the phylogenetically oldest neurotransmitters.  In the human body the largest crowd in front of serotonin is in the gastrointestinal tract.  About 90% of the entire human serotonin are stored here in the enterochromaffin cells. The serotonin in the blood is distributed almost exclusively on platelets. This Serotonin is produced by the enterochromaffin cells of the gastrointestinal tract and platelets in the blood.  Also basophilic granulocytes and mast cells can store and release serotonin.

In the central nervous system serotonin is located in particular in the neurons of the raphe nuclei.  A pathologically increased production, storage and release of serotonin may be common in neuroendocrine tumors of the gastrointestinal tract, carcinoids to be observed and are responsible for its characteristic accompanying symptoms.

Biochemistry
In humans and in animal serotonin, the amino acid L-tryptophan is a two-step reaction involving the enzyme built Aromatic L-amino acid decarboxylase. The first arises as an intermediate step, the non-proteinogenic amino acid 5-hydroxytryptophan.

The second step is a decarboxylation is the end product serotonin. Major production sites of serotonin are the central nervous system, liver, spleen and the enterochromaffin cells of the intestinal mucosa.  The biosynthesis of serotonin in plants differs in the order of the steps into animals.

Degradation
Neural serotonin after its release into the synaptic cleft is reabsorbed actively using the serotonin transporter SERT, a transport protein, and reused. The reduction of serotonin is primarily done by the enzyme monoamine oxidase (MAO) of type A and in a much lower degree of MAO type B. The product 5-hydroxy-indolyl-acetaldehyde is aldehyde dehydrogenase from further to 5-hydroxy-indolyl- acetic acid (5-HIAA compared). 5-hydroxy-indolyl-acetic acid, which in the urine can be demonstrated, is the main waste product of serotonin.
Features

In the human body there is a variety of serotonin functions in particular the cardiovascular system, the gastro-intestinal tract and nervous system.  At the molecular level, the functions of serotonin on at least 14 different serotonin receptors (5-HT receptors) proteins are grouped into seven families: 5-HT1 to 5-HT7. The 5-HT3 receptors consist of ion channels, all other known 5-HT receptors are G protein-coupled receptors.

Thanks to this variety of serotonin receptors, the tissue also is a distributed cell type and the organism responds to different serotonin concentrations and to start different signal transduction pathways.  These are the main cause for the often conflicting functions of serotonin in the body.
Cardiovascular system
The effects of serotonin on the cardiovascular system are complex and include both the contraction and the relaxation of blood vessels. While in the lungs and kidneys of people the vaso-constrictive effect is in the foreground, dominated in the skeletal muscles of the effect.

An intravascular injection of serotonin causes a tri-aphasic change in blood pressure.  After an initial drop in blood pressure occurs after a few seconds there is an increase in blood pressure and ends in prolonged hypotension.  For these effects, the receptors 5-HT1B, 5-HT2A, 5-HT2B and 5-HT7 are principal.  Depending on the blood vessel, this can cause a direct contraction (about 5-HT1B, 5-HT2A and 5-HT2B) orrelaxation of blood vessels (via 5-HT7).  Alternatively they indirectly relax blood vessels on the participation of the endothelium (via 5-HT1B and 5-HT2B).
Coagulation
Serotonin has both indirect and direct effects on blood coagulation. The platelets are also called platelets, the aggregation is an important component of blood clotting, and are not only the storage and release of serotonin, but bear serotonin receptors of type 5 HT2A.

Thanks to this, serotonin leads to an emptying of the granules of platelets and reinforced by other neurotransmitters, such as adenosine diphosphate or thrombin induced platelet aggregation.  In smaller blood vessels, it also contributes to wound healing through vasoconstriction.
Gastrointestinal system
Serotonin stimulates the intestinal peristalsis.  In the intestinal tissue this is 1-5 ppb.

Significantly increased values are available for a tumor enterochromaffin cells, i.e. at a small bowel carcinoid tumor.

This fact is used diagnostically. Cisapride is a serotonin agonist used as a Prokinetic, i.e. the promotion of the stomach, small intestine and large intestine.  Recently it was discovered that they detected odorants in food and subsequently released serotonin.  In the gastrointestinal tract there are 5-HT3 receptors and 5-HT4, a special role in the regulation of gastrointestinal motility.

Central nervous system
Serotonin, which is located in the central nervous system in the somata (cell bodies) and the serotoninergic nerves in raphe nuclei, emit their axons to all parts of the brain that affects directly or indirectly, almost all brain functions. The main functions of serotonin in the brain can cross the Naratriptan for migraine1blood-brain barrier and are formed so the spot has to include the control or influence the perception of sleep, temperature regulation, sensory and pain perception and processing of appetite, sexual behavior and hormone secretion.  Serotonin acts both as a neurotransmitter in the synaptic gap, and is diffusely distributed on the nerve endings.

Mood
The best known effects of serotonin on the central nervous system include effects on mood.  An increased level of serotonin in the brain, for example can be due to an overdose of selective serotonin reuptake inhibitors, leading to anxiety, euphoria and hallucinations. Depression can be attributed to a lack of serotonin or its precursor, the amino acid tryptophan.

Even fear and impulsive aggression may be due to a serotonin deficiency.  Serotonin is through a stimulation of certain regions of the cerebral cortex that are responsible for emotional regulation, mainly to the inhibition of impulsivity and aggressive behavior. Thereto, in particular serotonin receptors are of the type 5-HT1A and 5-HT1B.  For the soaring of serotonin and the hallucinogenic effects of serotonin agonists such as LSD is an activation of 5-HT2A receptors.  Serotonin due to its effects on mood in the vernacular is often referred to as the “happiness hormone”.

Sleep-wake rhythm
The effects of serotonin on sleep are partially contradictory and depend crucially on the part of the brain and the receptors involved.  The role of serotonin as an opponent of catecholamines in the initiation of sleep has been known since the 1950s.  A serotonin release was therefore associated with paradoxical sleep (REM sleep).  Surgical removal of the nuclei and inhibitors of serotonin synthesis, such as p-Chlorphenylalanin can be treated successfully by microinjection of serotonin or 5-hydroxytryptophan in the Hypnogen zones.

Also an increased intake of the amino acid tryptophan, can be formed from serotonin in the brain indicating sleep-effect. In contrast an increased activity of the raphe nuclei and increased serotonin secretion is observed during the recovery period.

Appetite
Serotonin is a neurotransmitter; its distribution in the brain is indirectly associated with food.  One factor is the concentration of free tryptophan in blood plasma.  A carbohydrate-rich diet leads to insulin secretion via an increase in tryptophan intake in the brain, which increased serotonin synthesis is associated with.  Serotonin is associated with a particular appetite-suppressing effect in combination.

In obese people the tryptophan levels in blood plasma and the serotonin levels are reduced in the brain.  Drugs increase the selective serotonin inhibitors, increase serotonin concentration in the brain leading to a loss of appetite as a side effect.  Selective activation of serotonin receptor subtype 5-HT1A, primarily is an auto-receptor controlling the release of serotonin through inhibition of serotonin from nerve endings to an increased appetite.  The actual effect of serotonin is largely due to the serotonin receptors 5-HT1B or 5-HT2C.

Pain
Serotonin, which is, for example, released from injured nerve cells, is a direct activator of a pain stimulus. Of greater importance is the effect of serotonin to increase descending neurons in the dorsal horn of the spinal cord or alleviate pain stimuli.

Sexual behaviour
Serotonin, which is distributed among other things, at the time of ejaculation in the hypothalamus, shows a primarily inhibitory effect on sexual behavior and sexual function.  Serotonin acts as an antagonist of dopamine.

Temperature Regulation
Serotonin is involved in the central nervous system in the regulation of body temperature.  Depending on the involved brain area and depending on the receptors involved, serotonin leads to an increase (hyperthermia) or a lowering of body temperature (hypothermia).  The hypothermic effect of serotonin is associated particularly with the activation of serotonin receptor subtype 5-HT7 in combination.
Pharmacology

Drugs that affect the release, the effect of the resumption and the degradation of serotonin, are used in many ways in therapy. The largest volume area of application of drugs with an effect on the serotonin system is for mental disorders.

Antidepressants

In the treatment of depression there are selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, fluvoxamine, paroxetine, sertraline and citalopram, which are all given a high priority. They are inhibitors of the serotonin transporter, leading to an increased concentration and a prolonged stay of serotonin in the synaptic cleft.

The effect of the older tricyclic antidepressants is based, at least in part, by inhibition of the serotonin transporter.  MAO inhibitors, such as tranylcypromine and moclobemide are also used as antidepressants and also owe their effectiveness in inhibition to the serotonin-degrading enzyme monoamine oxidase.
Neuroleptics

Diverging from the classical neuroleptics clinical features of many atypical antipsychotics can be explained by an inhibition of dopamine receptors in excess additional inhibition of serotonin receptor subtype 5-HT2A.  Clozapine, olanzapine and risperidone have a substantially improved effect on schizophrenia and a reduced frequency of extra-pyramidal motor side effects.

Appetite suppressants
The appetite-suppressing effect of serotonin has been exploited in various ways by an appetite suppressant.  Many of these drugs such as aminorex and fenfluramine show a direct stimulatory effect on the 5-HT2C receptor.  Another mechanism of action of some appetite suppressants such as sibutramine, is the increased concentration of serotonin to its receptors by inhibition of the serotonin transporter.
Migraine drugs

In migraine prophylaxis, at least until the advent of beta blockers, serotonin antagonists such as methysergide and pizotifen were used.
Antihypertensives (blood pressure lowering agents)
Antihypertensive agents of the 5-HT2A and the 5-HT1A agonist are used to treat high blood pressure.  Blood pressure lowering is not primarily explained by an interaction with serotonin receptors, but with an additional interaction with adrenoceptors.

Anticoagulant
The 5-HT2A antagonist Sarpogrelat is used as a platelet aggregation inhibitor.

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