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Histamine

Histamine is one of the compounds produced by the body's immune system in order to start inflammation. It actually plays several other roles, especially as a chemical neurotransmitter that helps messages pass from one nerve to another. Histamine is also needed inside the bowel.

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Basophils and mast cells produce histamine when invasive bodies are detected, in order to kick off the immune response. Both these types of cells are located in connective tissues near the skin. Once inflammation is started by histamine, capillary veins become permeable. This allows proteins and white blood cells to enter tissues and attack any foreign pathogens in the area.

Histamine is produced by mast cells and is one of the many chemicals stored inside the human body. It has the chemical structure C5H9N3 and is classified as a protein. Histamine is produced as part of the body's immune response. Various allergens, for example pollen, come in contact with the body and trigger the release of histamine in the area as an initial response. It is the first step in a reaction designed to limit the effects and irritation caused by the allergen. However, histamine itself can start an allergic reaction, which is a very strange effect. If the allergy is already severe, the additional response following a histamine release can have lethal consequences.

Scientists were able to produce synthetic histamine for the first time in 1907 but its actual role was only understood in 1911. It was named after the method of isolation, since it was an amine extracted from tissue ("histo"). In 1966, the receptor subtypes for histamine were described for the first time. The first antihistamine drugs are actually much older, being produced since 1943.

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Histamine is formed through the decarboxylation of amino acid histidine. The enzyme L-histidine decarboxylase serves as a chemical catalyst for this reaction. As a hydrophilic vasoactive amine, histamine has to be either stored or neutralized shortly after it is produced. Acetaldehyde dehydrogenase is the process that breaks it when the chemical is released at synapses. Severe allergic reactions can occur if histamine is allowed to build up in the synapses if there is a lack of this enzyme. Diamine oxidase and histamine-N-methyltransferase are the two other enzymes that break down histamine.

Functions in the body

Histamine plays several important roles and can be described chemically as an organic nitrogenous compound. Its main function is to start local immune responses but it is also an important neurotransmitter in the brain, spinal cord or inside the womb. It also regulates physiological function in the gut and is the main mediator of itching. Basophils and mast cells found in connective tissues produce and release histamine in the skin when any kinds of pathogens or toxins are detected. The role of histamine is to inflame the area, allowing white blood cells and proteins to exit the capillaries and neutralize the threats.

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Histamine only consists of 17 atoms, which is very small compared to other molecules that play a biologic role. Despite its size, it is very important and 23 different functions that use histamine have been discovered so far. This is due to histamine's binding versatility, which allows it to be involved in many different processes. It can interact and bind easily with various compounds, due to its chemical properties as a conformational, flexible and potentially charged molecule.

Histamine can be injected intravenously, which can trigger a drop in blood pressure because it forces vessels to dilate. This mechanism has been observed to play a key role in anaphylaxis. Scientists suspect that it happens after endothelial cells release compounds such as nitric oxide or endothelium-derived hyperpolarizing factors after histamine is produced in the area.

This chemical boosts vascular permeability, allowing liquids to move through the walls of capillaries into the tissues. This effect explains the wet nose and eyes that are typical of any allergic reaction. The mucous membranes inside the nasal cavity include mast cells loaded with IgE that allow allergens to bind on them. Several symptoms are associated with this reaction. Initially, glandular tissues start to release an unusual amount of fluids and the neural stimulation caused by histamine makes you sneeze. Histamine also makes capillaries expand and become permeable, which causes a serious nasal congestion.

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Histamine actually works as a neurotransmitter and the cell body neurons associated with it are located in the tuberomammillary nuclei, or the posterior hypothalamus area of the brain. Through the medial forebrain bundle, the histamine neurons reach the cortex and all other brain areas. These neurons play several important roles and are known to prevent sleep and boost concentration.

Antihistamine drugs that act as H1 histamine receptor antagonists are known to cause drowsiness once they reach the brain from the bloodstream. The sedative effect of new-generation drugs is much weaker, since they no longer enter the brain. However, these can sometimes have a stronger effect in individual cases, for example when used in combination with other drugs. The same sedative effect can happen naturally when the neurons that release histamine are destroyed or the synthesis of this chemical is inhibited. The H3 receptor antagonists act in an opposite way and increase wakefulness.

The neurons related to histamine are closely connected to alertness and sleep patterns. They become very active as you wake up and are slow when you are tired or relaxed. During REM or non-REM sleep, they become completely inactive.

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The gastric glands of the stomach include cells similar to enterochromaffin. These stimulate parietal cells by releasing histamine, which binds to their apical H2 receptor. The result is an increased absorption of both water and carbon dioxide from the blood, after parietal cells increase their activity. Carbonic anhydrase is the enzyme that transforms these compounds into carbonic acid. The acid then splits into hydrogen and ions of bicarbonate in the cytoplasm of the parietal cells. The bicarbonate ions make their way back to the bloodstream by passing through the basilar membrane, while the K+/H+ ATPase pump sends hydrogen molecules inside the stomach lumen. As soon as the stomach pH begins to drop, histamine is no longer released. Ranitidine and other antagonist drugs stop the binding of histamine by blocking the H2 receptor. In turn, a lower number of hydrogen ions are produced in this case.

Histamine is also involved in digestion because it is needed for the production of acid inside the stomach. Signals sent by the nervous system trigger the production of histamine from enterochromaffin-like cells inside the stomach, which are a particular type of cells. Parietal cells are them stimulated to start releasing acid after histamine binds to their H2 receptors. Heartburn drugs, also known as H2 receptor blockers, interfere with this process in order to limit acid production.

This chemical is known to have a double effect on neurons. It is able to stimulate them but can also protect them from stress and reactions such as denervation supersensitivity, ischemic lesions, convulsion or drug sensitization. Histamine might also be involved in the reactions that allow memory and learning functions inside the human brain.

Cimetidine, ranitidine, risperidone and other H2 receptor antagonists for histamine can cause side effects like lack of erection or poor libido, when used in long treatments. However, tests on males with psychogenic impotence have revealed that 74% of them had at least a partial erection after histamine was injected into their corpus cavernosum. Sexual problems can also occur after the production of testosterone is limited by H2 antagonists.

Patients who suffer from schizophrenia have an increased level of histamine metabolites in their cerebrospinal fluid and display a low rate of H1 receptor binding sites. Some alternative treatments for mental diseases try to exploit this fact. Since people with schizophrenia have altered histamine levels, these new therapies aim to boost histamine production.

Histamine is also being investigated as a potential treatment for multiple sclerosis, a disease that can't be cured. Scientists have discovered that H receptors seem to influence the evolution of this condition. One research paper has concluded that H1 and H4 receptors aren't useful in the treatment of sclerosis. This is because the penetration of external cells inside the central nervous system is increased by these receptors, which allow greater permeability of the blood-brain barrier. This can make multiple sclerosis symptoms worse, as well as cause inflammation.

However, H2 and H3 receptors appear to help in the treatment of multiple sclerosis, mainly because histamine appears to influence T-cell differentiation. The body's immune system starts attacking the myelin sheaths of nerve cells in cases of multiple sclerosis. In time, nervous signals start to get lost and eventually the nerves are almost destroyed. Histamine helps T-cells identify their own body cells and makes them attack pathogens instead, as they are designed to do.

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