Histamine

Dr. Muzaffar Abbas

Chemistry & & Pharmacokinetics
Histamine is a hydrophilic molecule consisting of an
imidazole ring and an amino group connected by two
methylene groups.

•Histamine is formed by decarboxylation of the

amino acid l-histidine, a reaction catalyzed in
mammalian tissues by the enzyme histidine
decarboxylase.

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 Histamine is synthesized from the amino acid
histidine through oxidative decarboxylation by
histidine-decarboxylase

Histamine synthesis and metabolism. Histidine is taken up in a varicosity and

decarboxylated; histamine is transported into a vesicle, released, and methylated.
 Almost all mammalian tissues contain histamine.
 The mast cell is the predominant storage site for
histamine in most tissues; in the blood, it is the
basophil.
 The concentration of histamine is particularly
high in tissues that contain large numbers of mast
cells, such as skin, bronchial tree mucosa, and
intestinal mucosa.
 The major metabolic pathways involve conversion
to N-methylhistamine, methylimidazoleacetic acid,
and imidazoleacetic acid (IAA). Certain
neoplasms (systemic mastocytosis, urticaria
pigmentosa, gastric carcinoid, and occasionally
myelogenous leukemia) are associated with 4
of mast cells or basophils and with increased
excretion of histamine and its metabolites.
Non-mast cell histamine is found in several tissues,
including the brain & enterochromaffin-like (ECL)
cells of the fundus of the stomach.

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Storage & Release of Histamine
A. Immunologic Release
Mast cell and basophil if sensitized by IgE
antibodies attached to their surface membranes,
degranulate explosively when exposed to the
appropriate antigen.
In humans, mast cells in skin and basophils show
this negative feedback mechanism; lung mast cells do
not.
B. Chemical and Mechanical Release
Tubocurarine, succinylcholine, morphine, some
antibiotics, radiocontrast media, and certain
carbohydrate plasma expanders may elicit the
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response. The phenomenon may account for
unexpected anaphylactoid reactions.
Vancomycin-induced “red-man syndrome”
involving upper body and facial flushing and
hypotension may be mediated through histamine
release.
Some venoms, such as that of the wasp, contain
potent histamine-releasing peptides.

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 The histaminergic system in the human brain. The histaminergic fibers emanating from the
tuberomamillary nucleus project to and arborize in the whole central nervous system
 In the brain, the histaminergic neuron bodies are
concentrated in the tuberomammillary nucleus of
the hypothalamus (TMN).
 There are about 64,000 histaminergic neurons in
the human brain.
 TMN sends fibers to almost all regions, including
the cerebral cortex and the spinal cord, amygdala,
substantia nigra (SN), striatum, hippocampus and
thalamus.
 In addition to histaminergic neurons, brain
histamine is produced in mast cell, mainly present
in the pia mater, thalamus and hypothalamus and
the rate of histamine synthesis, release and
metabolism in mast cells is much slower than in
histaminergic neurons. Moreover, microglia and
ependymal cells in the brain may also produce
histamine, but the role of these histamines has not
been fully determined.
Histamine Receptors
There are mainly four known histamine receptor
subtypes (H1R-H4R), all of which belong to the large
family of G-protein-coupled receptors (GPCRs).
Histamine H1 Receptor (H1R)
Histamine H1 receptor (H1R) is widely distributed
in the central nervous system, especially in the brain
regions known to regulate arousal state and sleep-
wakefulness, such as thalamus, cortex, cholinergic
nuclei, locus coeruleus and raphe nucleus.
Intracellularly, the H1R is coupled to Gq/11 proteins
and stimulates phospholipase C (PLC), resulting in
the activation of neurons and astrocytes. The
activated PLC catalyzes the hydrolysis of
phosphatidylinositol-4,5-biphosphate (PIP2) into two
second messengers, inositol triphosphate (IP3) and
diacylglycerol (DAG).
 IP3 induces the release of stored Ca2+ from
intracellular stores into the cytoplasm and DAG
mediates the activation of protein kinase C (PKC).
 Additionally, the activation of H1R also lead to the
production of cyclic guanosine monophosphate
(cGMP) and nitric oxide (NO) and increase the
activity of phospholipase A2 (PLA2), which
induces arachidonic acid formation.
Histamine H2 Receptor (H2R)
Histamine H2 receptor (H2R) is mainly expressed in
several brain areas including basal ganglia,
hippocampus, amygdala and cerebral cortex.
The H2R is coupled to Gs proteins and then
stimulates adenylyl cylase, inducing an increase in
intracellular cyclic adenosine monophosphate
(cAMP) production. The increase in cAMP activates
protein kinase A (PKA), which in turn
phosphorylates its target proteins in the cytosol, cell
membrane or translocate to the nucleus, and then
activate the cAMP response element-binding protein
(CREB).
H2R activation also blocks a Ca2+-activated
potassium conductance, inhibits PLA2 and release of
arachidonic acid, which may explain why H1R and
H2R have opposite physiological responses in many
tissues.
Histamine H3 Receptor (H3R)
Histamine H3 receptor (H3R) is widely distributed
in the central nervous system in the cortex,
hippocampus and caudate nucleus, followed by the
anterior olfactory nucleus, amygdala, bed nucleus of
stria terminalis, cerebellum and thalamus.
As a presynaptic autoreceptor on histaminergic
neurons, the H3R mediates feedback inhibition of the
release and synthesis of histamine. The H3R also
distributes on the presynaptic membrane of non-
histaminergic neurons and regulates the release of
other neurotransmitters, such as dopamine,
glutamate, GABA and acetylcholine.
 The H3R is coupled to Gi/o proteins and plays an
important role in the transduction process of
downstream signaling pathways. The activation of
H3R inhibits the adenylyl cyclase, decreasing the
production of cAMP from adenosine triphosphate
(ATP).
 H3R activation also leads to inhibition of high-
voltage activated calcium channels, which reduces
transmitter release in presynaptic terminals.
 In addition, H3R activates phosphorylation of the
Akt/GSK-3 beta pathway, inwardly rectifying K+
channels, phospholipase C, phosphatidylinositide
3-kinases (PI3K) and mitogen-activated protein
kinases (MAPK)
Histamine H4 Receptor (H4R, Gi coupled)
Histamine H4 receptor (H4R) is recently identified
as a new member of the histamine receptor family,
which is mainly expressed on the cells of the
hematopoietic lineage and immune cells, such as
mast cells, eosinophils and dendritic cells.
H4R is also reported present in microglia with
unconvincing evidence, whose function is still
unclear.
At present, the research on H4R mainly focuses on
its role in the inflammatory process mediated by
histamine.
Histamine and Type I hypersensitivity reaction

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 Histamine and Type I hypersensitivity reaction
Exposure to an allergen activates TH2 cells that
stimulate B cells to form IgE-secreting plasma cells.
The secreted IgE molecules bind to IgE-specific Fc
receptors (FcεRI) on mast cells and blood basophils.
(Many molecules of IgE with various specificities
can bind to the FcεRI.)
Second exposure to the allergen leads to cross-
linking of the bound IgE, triggering the release of
pharmacologically active mediators (vasoactive
amines) from mast cells and basophils.
The mediators cause smooth muscle contraction,
increased vascular permeability, and vasodilation.
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General mechanism underlying an immediate type I hypersensitivity reaction.
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Signaling pathways initiated by IgE allergen cross-linking. 22
Common allergens associated with type I hypersensitivity 23
Histamine and acid secretion

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Figure: External and internal anatomy of the stomach. The four regions of the stomach are the
cardia, fundus, body, and pylorus.
Figure: Histology of the stomach. Gastric juice is the combined secretions of mucous cells,
parietal cells, and chief cells.
Figure: Histology of the stomach. Gastric juice is the combined secretions of mucous cells,
parietal cells, and chief cells.
Physiology of acid secretion
The parietal cell contains receptors for gastrin (CCK-
B/(CCk)2), histamine (H2), and acetylcholine
(muscarinic, M3).
When acetylcholine (from vagal postganglionic
nerves) and gastrin (released from antral G cells into
the blood) bind to the parietal cell receptors, they
cause an increase in cytosolic calcium, which in turn
stimulates protein kinases that stimulate acid secretion
from a H+/K+-ATPase (the proton pump) on the
canalicular surface.
Histamine (paracrine secretion) binds to the H2
receptor on the parietal cell, resulting in activation of
adenylyl cyclase, which increases intracellular 28
cyclic adenosine monophosphate (cAMP) and
activates protein kinases that stimulate acid secretion
by the H+/K+-ATPase.
In humans, it is believed that the major effect of
gastrin upon acid secretion is mediated indirectly
through the release of histamine from ECL cells rather
than through direct parietal cell stimulation. In
contrast, acetylcholine provides potent direct parietal
cell stimulation.

Many non-specific NSAIDs cause gastric bleeding and erosions by inhibiting cyclo-oxygenase-1,
the enzyme responsible for synthesis of protective prostaglandins. More selective cyclo-
oxygenase-2 inhibitors such as celecoxib appear to cause less stomach damage. 29
Physiology of acid secretion

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Physiology of acid secretion

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A schematic illustration of the secretion of hydrochloric acid by the gastric parietal cell.
Secretion involves a proton pump (P), which is an H+-K+-ATPase, a symport carrier (C) for K+
and Cl−, and an antiport (A), which exchanges Cl− and HCO3−. An additional Na+/H+ antiport
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situated at the interface with the plasma may also have a role (not shown).
The Histaminergic System in Neuropsychiatric
Disorders
The Histaminergic System in Neuropsychiatric
Disorders
The histaminergic system plays an important role in
regulating various functions of the brain, such as
sleep and wakefulness, learning and memory, feeding
and energy balance.
Moreover, histaminergic system plays an important
role in neuropsychiatric disorders, including
narcolepsy, schizophrenia, Alzheimer’s disease,
Tourette’s syndrome and Parkinson’s disease.
Sleep Disorders
Histamine system is strongly suggested to play an
essential role in modulating sleep and wake behavior
via H1R and/or H3R.
Histamine release is found to have a circadian
rhythm, which is responsible for the modulation of
sleep and wakefulness.
The histaminergic TMN neurons fire only during
wakefulness and their activities are related to a high
level of vigilance. In contrast, they cease firing and
then remain quiescent during slow-wave sleep (SWS)
and rapid eye movement sleep.
Additionally, the expression of immediate-early
gene c-fos (a maker of neuronal activation) in
histaminergic TMN neurons is higher during periods
of wakefulness.
The ventrolateral preoptic area (VLPO) of the
hypothalamus is essential for sleep regulation and
anatomical studies have shown that the VLPO and
TMN are connected. The release of histamine from
TMN neurons by using photostimulation indirectly
suppresses sleep-active VLPO neurons through the
activation of the GABAergic interneuron.
In addition, the orexin/hypocretin (hypocretin
neuropeptide precursor, HCRT) neurons are one
important input to innervate and excite the TMN
neurons during wakefulness.
 Infusion of orexin A produces a significant
Figure. Hypothalamus. Selected portions of the hypothalamus and a three-dimensional
representation of hypothalamic nuclei are shown (after Netter). The hypothalamus controls many
body activities and is an important regulator of homeostasis.
increase in wakefulness, which dependeds on the
activation of histaminergic neurotransmission
mediated by H1R.
On the other hand, histamine also plays a regulatory
role on the developing Hypocretin Neuropeptide
Precursor (HCRT) system via H1R. It has been
suggested that activity of TMN histaminergic
neurons is important for enhancing arousal under
certain conditions, such as exposure to a novel
environment.
It was found that the tonic firing of histaminergic
neurons is necessary for the maintenance of arousal
during wakefulness, and their silencing is sufficient
to impair arousal and induce Sturge-Weber syndrome
(SWS) rapidly and selectively.
 Narcolepsy is a disabling and chronic neurological
disorder primarily characterized by irresistible
sleep episodes and cataplexy. Given
histaminergic system comprises a major
component of the arousal system and regulates
sleep-wake cycle, its effect on narcolepsy has been
extensively studied. Several studies have
confirmed reduced cerebrospinal fluid (CSF)
histamine levels in human narcolepsy especially in
hypocretin-deficient narcolepsy.
 The H3R antagonist/inverse agonist pitolisant has
been approved in the EU for the treatment of
narcolepsy with or without cataplexy in adult
patients and in the USA for the treatment of
excessive daytime sleepiness in adult patients with
narcolepsy. Additionally, clinical studies have
confirmed the long-term safety and therapeutic effect
of pitolisant on daytime sleepiness, cataplexy,
hallucinations and sleep paralysis repeatedly.
.

Figure 1. A schematic diagram of circuits regulating the sleep and wakefulness by the
TMN histaminergic system. BF, basal forebrain; Ctx, cortex; DR, dorsal raphe; LC, locus
coeruleus; LDT/PPT, laterodorsal/pedunculopontine tegmental nuclei; LH, lateral
hypothalamic; POA, preoptic area; Str, striatum; TMN, tuberomammillary nucleus; VTA,
ventral tegmental area
Schizophrenia
Psychiatric disorders, such as schizophrenia, has
attracted the attention of researchers.
Basic science and clinical studies suggest a role of
brain histamine in schizophrenia. Schizophrenics,
especially those with predominantly negative
symptoms, have elevated levels of N-tele-
methylhistamine, the major histamine metabolite in
the cerebrospinal fluid .
Indeed, some second-generation antipsychotics,
including clozapine and olanzapine, have potent
antagonistic effects on H1R. However, it remains
incompletely understood that the ability of
antipsychotics to block H1R is responsible for the
therapeutic effects or the side effects of these
compounds.
Antipsychotics are widely used in the treatment of
schizophrenia and one of the common adverse effects
is weight gain, which is associated with increased
risk of obesity in patients with schizophrenia.
Betahistine, a weak partial H1R agonist and H3R
antagonist, seem to reduce weight gain caused by
antipsychotic drugs.
Eating Disorders and Metabolic Syndrome
The brain histamine system controls appetite,
feeding rhythms, and energy metabolism and thus
may play a role in eating disorders and metabolic
syndromes.
Compulsive eating in anorexia nervosa, bulimia, or
binge-eating syndrome likely relates to histamine
effects on brain reward systems. H3R ligands are
clinically tested for application in eating disorders.
Histamine- and histamine receptor-deficient animals
show hyperphagia and disruption of feeding circadian
rhythm and develop obesity, diabetes mellitus,
hyperlipidemia, hyperinsulinemia, and disturbance of
thermoregulation and cardiovascular functions,
fundamental marks of metabolic syndromes.
 Pruritus and Pain
Histamine mediates itch and modulates pain in the
periphery and in the CNS.
In the periphery histamine specifically activates and
sensitizes itch-specific nociceptive C fibers.
Both histamine and opioids can generate itch, while
scratch-induced pain and antidepressants with
antihistaminic properties can abolish itch.
In contrast to histamine actions on nociceptive
fibers, the central histamine system plays a role in
antinociception and stress-induced analgesia.
Antihistaminic properties of antidepressants may in
turn contribute to the analgesic effects of these drugs
 Analgesic or nociceptive effects of many
neuropeptides rely on histaminergic transmission.
Morphine can increase the release and metabolism
of brain histamine when applied systemically or
more locally in the periaquaductal grey and
slightly depolarizes TMN neurons, whereas the
opioid peptide nociceptin causes a
hyperpolarization, which may contribute to the
antagonism of opioid-induced analgesia.
 Increases in brain histamine produced by loading
with L-histidine or application of HNMT
inhibitors or H3R antagonists have analgesic
effects. H3R represent a promising target in pain
therapy
Depression
Many antidepressants have H1R and H2R
antihistaminic properties, which likely do not account
for their therapeutic efficacy but a number of serious
adverse effects, including sedation, weight gain, and
cardiovascular dysfunctions.
Dose-dependent H1 antihistaminic properties of
antidepressants may be useful to treat insomnia and
endogenous histamine, and H1R agonists have
antidepressant-like properties.
Some of the first-generation antihistamines act as
serotonin reuptake inhibitors in animals and humans
Modulation of histaminergic transmission may thus
prove to be useful in the treatment of depression and
related mood disorders.