Histamine is an organic nitrogenous compound involved in local immune
responses, as well as regulating physiological function in the gut and
acting as a neurotransmitter for the brain, spinal cord, and
Histamine is involved in the inflammatory response and
has a central role as a mediator of itching. As part of an immune
response to foreign pathogens, histamine is produced by basophils and
by mast cells found in nearby connective tissues.
the permeability of the capillaries to white blood cells and some
proteins, to allow them to engage pathogens in the infected
2 Synthesis and metabolism
3 Storage and release
4 Mechanism of action
5 Roles in the body
Vasodilation and a fall in blood pressure
5.2 Effects on nasal mucous membrane
5.3 Sleep-wake regulation
Gastric acid release
5.5 Protective effects
5.6 Erection and sexual function
5.8 Multiple sclerosis
8 See also
10 External links
Histamine base, obtained as a mineral oil mull, melts at
83–84 °C. Hydrochloride and phosphorus salts form
white hygroscopic crystals and are easily dissolved in water or
ethanol, but not in ether. In aqueous solution, histamine exists in
two tautomeric forms: Nπ-H-histamine and Nτ-H-histamine. The
imidazole ring has two nitrogens. The nitrogen farthest away from the
side chain is the 'tele' nitrogen and is denoted by a lowercase tau
sign. The nitrogen closest to the side chain is the 'pros' nitrogen
and is denoted by the pi sign. The position of the nitrogen with the
hydrogen on it determines how the tautomer is named. If the nitrogen
with the hydrogen is in the tele position, then histamine is in the
tele-tautomer form. The tele-tautomer is preferred in solution.
Tautomers of histamine
Histamine has two basic centres, namely the aliphatic amino group and
whichever nitrogen atom of the imidazole ring does not already have a
proton. Under physiological conditions, the aliphatic amino group
(having a pKa around 9.4) will be protonated, whereas the second
nitrogen of the imidazole ring (pKa ≈ 5.8) will not be
protonated. Thus, histamine is normally protonated to a singly
Histamine is a monoamine neurotransmitter.
Synthesis and metabolism
Histamine is derived from the decarboxylation of the amino acid
histidine, a reaction catalyzed by the enzyme L-histidine
decarboxylase. It is a hydrophilic vasoactive amine.
Conversion of histidine to histamine by histidine decarboxylase
Once formed, histamine is either stored or rapidly inactivated by its
primary degradative enzymes, histamine-N-methyltransferase or diamine
oxidase. In the central nervous system, histamine released into the
synapses is primarily broken down by histamine-N-methyltransferase,
while in other tissues both enzymes may play a role. Several other
MAO-B and ALDH2, further process the immediate
metabolites of histamine for excretion or recycling.
Bacteria also are capable of producing histamine using histidine
decarboxylase enzymes unrelated to those found in animals. A
non-infectious form of foodborne disease, scombroid poisoning, is due
to histamine production by bacteria in spoiled food, particularly
fish. Fermented foods and beverages naturally contain small quantities
of histamine due to a similar conversion performed by fermenting
bacteria or yeasts.
Sake contains histamine in the 20–40 mg/L
range; wines contain it in the 2–10 mg/L range.
Storage and release
Most histamine in the body is generated in granules in mast cells and
in white blood cells (leukocytes) called basophils.
Mast cells are
especially numerous at sites of potential injury — the nose, mouth,
and feet, internal body surfaces, and blood vessels. Non-mast cell
histamine is found in several tissues, including the brain, where it
functions as a neurotransmitter. Another important site of histamine
storage and release is the enterochromaffin-like (ECL) cell of the
The most important pathophysiologic mechanism of mast cell and
basophil histamine release is immunologic. These cells, if sensitized
IgE antibodies attached to their membranes, degranulate when
exposed to the appropriate antigen. Certain amines and alkaloids,
including such drugs as morphine, and curare alkaloids, can displace
histamine in granules and cause its release. Antibiotics like
polymyxin are also found to stimulate histamine release.
Histamine release occurs when allergens bind to mast-cell-bound IgE
antibodies. Reduction of
IgE overproduction may lower the likelihood
of allergens finding sufficient free
IgE to trigger a
mast-cell-release of histamine.
Mechanism of action
In humans, histamine exerts its effects primarily by binding to G
protein-coupled histamine receptors, designated H1 through H4. As
of 2015, histamine is believed to activate ligand-gated chloride
channels in the brain and intestinal epithelium.
Biological targets of histamine in the human body
G-protein coupled receptor
Histamine H1 receptor
CNS: Expressed on the dendrites of the output neurons of the
histaminergic tuberomammillary nucleus, which projects to the dorsal
raphe, locus coeruleus, and additional structures.
Periphery: Smooth muscle, endothelium, sensory nerves
Sleep-wake cycle (promotes wakefulness), body temperature,
nociception, endocrine homeostasis, regulates appetite, involved in
Periphery: Causes bronchoconstriction, bronchial smooth muscle
contraction, vasodilation, promotes hypernociception (visceral
hypersensitivity), involved in itch perception and urticaria.
Histamine H2 receptor
Dorsal striatum (caudate nucleus and putamen), cerebral cortex
(external layers), hippocampal formation, dentate nucleus of the
Periphery: Located on parietal cells, vascular smooth muscle cells,
neutrophils, mast cells, as well as on cells in the heart and uterus
CNS: Not established (note: most known H2 receptor ligands are unable
to cross the blood–brain barrier in sufficient concentrations to
allow for neuropsychological and behavioral testing)
Periphery: Primarily involved in vasodilation and stimulation of
gastric acid secretion. Modulates gastrointestinal function.
Histamine H3 receptor
Located in the central nervous system and to a lesser extent
peripheral nervous system tissue
Autoreceptor and heteroreceptor functions: decreased neurotransmitter
release of histamine, acetylcholine, norepinephrine, serotonin
Modulates nociception, gastric acid secretion, and food intake.
Histamine H4 receptor
Located primarily on basophils and in the bone marrow. It is also
expressed in the thymus, small intestine, spleen, and colon.
Plays a role in mast cell chemotaxis, itch perception, cytokine
production and secretion, and visceral hypersensitivity. Other
functions (inflammation, allergy, cognition, etc.) have not been fully
Ligand-gated ion channel
Histamine-gated chloride channel
Putatively: CNS (hypothalamus, thalamus) and intestinal epithelium
Brain: Produces fast inhibitory postsynaptic potentials
Intestinal epithelium: chloride secretion (associated with secretory
Roles in the body
Although histamine is small compared to other biological molecules
(containing only 17 atoms), it plays an important role in the body. It
is known to be involved in 23 different physiological functions.
Histamine is known to be involved in many physiological functions
because of its chemical properties that allow it to be versatile in
binding. It is Coulombic (able to carry a charge), conformational, and
flexible. This allows it to interact and bind more easily.
Vasodilation and a fall in blood pressure
When injected intravenously, histamine causes most blood vessels to
dilate, and hence causes a fall in the blood pressure. This is a
key mechanism in anaphylaxis, and is thought to be caused when
histamine releases nitric oxide, endothelium-derived hyperpolarizing
factors and other compounds from the endothelial cells.
Effects on nasal mucous membrane 
Increased vascular permeability causes fluid to escape from
capillaries into the tissues, which leads to the classic symptoms of
an allergic reaction: a runny nose and watery eyes. Allergens can bind
to IgE-loaded mast cells in the nasal cavity's mucous membranes. This
can lead to three clinical responses:
sneezing due to histamine-associated sensory neural stimulation
hyper-secretion from glandular tissue
nasal congestion due to vascular engorgement associated with
vasodilation and increased capillary permeability
Histamine is released as a neurotransmitter. The cell bodies of
histamine neurons are found in the posterior hypothalamus, in the
tuberomammillary nuclei. From here, these neurons project throughout
the brain, including to the cortex, through the medial forebrain
Histamine neurons increase wakefulness and prevent sleep.
Classically, antihistamines (H1 histamine receptor antagonists) which
cross the blood-brain barrier produce drowsiness. Newer antihistamines
are designed to not cross into the brain and thus are less likely to
cause sedation, although individual reactions, concomitant medications
and dosage may increase the sedative effect. Similar to the effect of
older antihistamines, destruction of histamine releasing neurons, or
inhibition of histamine synthesis leads to an inability to maintain
vigilance. Finally, H3 receptor antagonists increase wakefulness.
Histaminergic neurons have a wakefulness-related firing pattern. They
fire rapidly during waking, fire more slowly during periods of
relaxation/tiredness and completely stop firing during REM and NREM
Gastric acid release
Enterochromaffin-like cells, located within the gastric glands of the
stomach, release histamine that stimulates nearby parietal cells by
binding to the apical H2 receptor. Stimulation of the parietal cell
induces the uptake of carbon dioxide and water from the blood, which
is then converted to carbonic acid by the enzyme carbonic anhydrase.
Inside the cytoplasm of the parietal cell, the carbonic acid readily
dissociates into hydrogen and bicarbonate ions. The bicarbonate ions
diffuse back through the basilar membrane and into the bloodstream,
while the hydrogen ions are pumped into the lumen of the stomach via a
K+/H+ ATPase pump.
Histamine release is halted when the pH of the
stomach starts to decrease. Antagonist molecules, like ranitidine,
block the H2 receptor and prevent histamine from binding, causing
decreased hydrogen ion secretion.
While histamine has stimulatory effects upon neurons, it also has
suppressive ones that protect against the susceptibility to
convulsion, drug sensitization, denervation supersensitivity, ischemic
lesions and stress. It has also been suggested that histamine
controls the mechanisms by which memories and learning are
Erection and sexual function
Libido loss and erectile failure can occur during treatment with
histamine H2 receptor antagonists such as cimetidine, ranitidine, and
risperidone. The injection of histamine into the corpus cavernosum
in men with psychogenic impotence produces full or partial erections
in 74% of them. It has been suggested that H2 antagonists may
cause sexual difficulties by reducing the uptake[clarification needed]
Metabolites of histamine are increased in the cerebrospinal fluid of
people with schizophrenia, while the efficiency of H1 receptor binding
sites is decreased. Many atypical antipsychotic medications have the
effect of increasing histamine production, because histamine levels
seem to be imbalanced in people with that disorder.
Histamine therapy for treatment of multiple sclerosis is currently
being studied. The different H receptors have been known to have
different effects on the treatment of this disease. The H1 and H4
receptors, in one study, have been shown to be counterproductive in
the treatment of MS. The H1 and H4 receptors are thought to increase
permeability in the blood-brain barrier, thus increasing infiltration
of unwanted cells in the central nervous system. This can cause
inflammation, and MS symptom worsening. The H2 and H3 receptors are
thought to be helpful when treating MS patients.
Histamine has been
shown to help with T-cell differentiation. This is important because
in MS, the body's immune system attacks its own myelin sheaths on
nerve cells (which causes loss of signaling function and eventual
nerve degeneration). By helping T cells to differentiate, the T cells
will be less likely to attack the body's own cells, and instead attack
As an integral part of the immune system, histamine may be involved in
immune system disorders and allergies.
Mastocytosis is a rare
disease in which there is a proliferation of mast cells that produce
The properties of histamine, then called β-iminazolylethylamine, were
first described in 1910 by the British scientists Henry H. Dale and
P.P. Laidlaw. By 1913 the name histamine was in use, using
combining forms of histo- + amine, yielding "tissue amine".
"H substance" or "substance H" are occasionally used in medical
literature for histamine or a hypothetical histamine-like diffusible
substance released in allergic reactions of skin and in the responses
of tissue to inflammation.
Hay fever (allergic rhinitis)
Histamine receptor antagonist
Red wine headache
Scombroid food poisoning
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Histamine MS Spectrum
Histamine bound to proteins in the PDB
Histamine receptor modulators
Antagonists: First-generation: 4-Methyldiphenhydramine
Others: Atypical antipsychotics (e.g., aripiprazole, asenapine,
brexpiprazole, clozapine, iloperidone, olanzapine, paliperidone,
quetiapine, risperidone, RP-5063, ziprasidone, zotepine)
Phenylpiperazine antidepressants (e.g., hydroxynefazodone, nefazodone,
Tetracyclic antidepressants (e.g., amoxapine, loxapine, maprotiline,
mianserin, mirtazapine, oxaprotiline)
Tricyclic antidepressants (e.g., amitriptyline, butriptyline,
clomipramine, desipramine, dosulepin (dothiepin), doxepin, imipramine,
iprindole, lofepramine, nortriptyline, protriptyline, trimipramine)
Typical antipsychotics (e.g., chlorpromazine, flupenthixol,
fluphenazine, loxapine, perphenazine, prochlorperazine, thioridazine,
See also: Receptor/signaling modulators • Monoamine metabolism
modulators • Monoamine reuptake inhibitors
Major excitatory/inhibitory systems: Glutamate system: Agmatine
Aspartic acid (aspartate)
Glutamic acid (glutamate)
Serine; GABA system: GABA
Glycine system: α-Alanine
Taurine; GHB system: GHB
Biogenic amines: Monoamines: 6-OHM
Serotonin (5-HT); Trace amines: 3-Iodothyronamine
p-Tyramine; Others: Histamine
Neuropeptides: See here instead.
2-AGE (noladin ether)
Neurosteroids: See here instead.
Adenosine system: Adenosine
Cholinergic system: Acetylcholine
Carbon monoxide (CO)
Hydrogen sulfide (H2S)
Nitric oxide (NO); Candidates: Acetaldehyde
Carbonyl sulfide (COS)
Nitrous oxide (N2O)
Sulfur dioxide (SO2)
Human trace amine-associated receptor ligands
Classical monoamine neurotransmitters
† References for all endogenous human
TAAR1 ligands are provided at
List of trace amines
‡ References for synthetic
TAAR1 agonists can be found at
in the associated compound articles. For
TAAR5 agonists and
inverse agonists, see TAAR for references.
See also: Receptor/signaling modulators