Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin,
is an organic chemical in the catecholamine family that functions in
the brain and body as a hormone and neurotransmitter. The name
"noradrenaline", derived from Latin roots meaning "at/alongside the
kidneys", is more commonly used in the United Kingdom; in the United
States, "norepinephrine," derived from Greek roots having that same
meaning, is usually preferred. "Norepinephrine" is also the
international nonproprietary name given to the drug. Regardless of
which name is used for the substance itself, parts of the body that
produce or are affected by it are referred to as noradrenergic.
In the brain, norepinephrine is produced in nuclei that are small yet
exert powerful effects on other brain areas. The most important of
these nuclei is the locus coeruleus, located in the pons. Outside the
brain, norepinephrine is used as a neurotransmitter by sympathetic
ganglia located near the spinal cord or in the abdomen, and it is also
released directly into the bloodstream by the adrenal glands.
Regardless of how and where it is released, norepinephrine acts on
target cells by binding to and activating noradrenergic receptors
located on the cell surface.
The general function of norepinephrine is to mobilize the brain and
body for action.
Norepinephrine release is lowest during sleep, rises
during wakefulness, and reaches much higher levels during situations
of stress or danger, in the so-called fight-or-flight response. In the
brain, norepinephrine increases arousal and alertness, promotes
vigilance, enhances formation and retrieval of memory, and focuses
attention; it also increases restlessness and anxiety. In the rest of
the body, norepinephrine increases heart rate and blood pressure,
triggers the release of glucose from energy stores, increases blood
flow to skeletal muscle, reduces blood flow to the gastrointestinal
system, and inhibits voiding of the bladder and gastrointestinal
A variety of medically important drugs work by altering the actions of
Norepinephrine itself is widely used as an
injectable drug for the treatment of critically low blood pressure.
Beta blockers, which counter some of the effects of norepinephrine,
are frequently used to treat glaucoma, migraine, and a range of
cardiovascular problems. Alpha blockers, which counter a different set
of norepinephrine effects, are used to treat several cardiovascular
and psychiatric conditions. Alpha-2 agonists often have a sedating
effect, and are commonly used as anesthesia-enhancers in surgery, as
well as in treatment of drug or alcohol dependence. Many important
psychiatric drugs exert strong effects on norepinephrine systems in
the brain, resulting in side-effects that may be helpful or harmful.
2 Biochemical mechanisms
3.1 Cellular effects
3.1.1 Storage, release, and reuptake
3.2 Sympathetic nervous system
3.3 Central nervous system
4.1 Beta blockers
4.2 Alpha blockers
4.3 Alpha-2 agonists
4.4 Stimulants and antidepressants
5 Diseases and disorders
5.1 Sympathetic hyperactivation
5.5 Autonomic failure
6 Comparative biology and evolution
Norepinephrine is a catecholamine and a phenethylamine. Its
structure differs from that of epinephrine only in that epinephrine
has a methyl group attached to its nitrogen, whereas the methyl group
is replaced by a hydrogen atom in norepinephrine. The prefix nor-
is derived as an abbreviation of the word "normal", used to indicate a
Biosynthetic pathways for catecholamines and trace amines in the human
Norepinephrine is synthesized from dopamine in the human body by the
dopamine β-hydroxylase (DBH) enzyme.
Norepinephrine is synthesized from the amino acid tyrosine by a series
of enzymatic steps in the adrenal medulla and postganglionic neurons
of the sympathetic nervous system. While the conversion of tyrosine to
dopamine occurs predominantly in the cytoplasm, the conversion of
dopamine to norepinephrine by dopamine β-monooxygenase occurs
predominantly inside neurotransmitter vesicles. The metabolic
Thus the direct precursor of norepinephrine is dopamine, which is
synthesized indirectly from the essential amino acid phenylalanine or
the non-essential amino acid tyrosine. These amino acids are found
in nearly every protein and, as such, are provided by ingestion of
protein-containing food, with tyrosine being the most common.
Phenylalanine is converted into tyrosine by the enzyme phenylalanine
hydroxylase, with molecular oxygen (O2) and tetrahydrobiopterin as
Tyrosine is converted into
L-DOPA by the enzyme tyrosine
hydroxylase, with tetrahydrobiopterin, O2, and probably ferrous iron
(Fe2+) as cofactors.
L-DOPA is converted into dopamine by the
enzyme aromatic L-amino acid decarboxylase (also known as DOPA
decarboxylase), with pyridoxal phosphate as a cofactor.
then converted into norepinephrine by the enzyme dopamine
β-monooxygenase (formerly known as dopamine β-hydroxylase), with O2
and ascorbic acid as cofactors.
Norepinephrine itself can further be converted into epinephrine by the
enzyme phenylethanolamine N-methyltransferase with
S-adenosyl-L-methionine as cofactor.
In mammals, norepinephrine is rapidly degraded to various metabolites.
The initial step in the breakdown can be catalyzed by either of the
enzymes monoamine oxidase (mainly monoamine oxidase A) or COMT.
From there the breakdown can proceed by a variety of pathways. The
principal end products are either
Vanillylmandelic acid or a
conjugated form of MHPG, both of which are thought to be biologically
inactive and are excreted in the urine.
Norepinephrine degradation. Metabolizing enzymes are shown in
Main article: Adrenergic receptor
Adrenergic receptors in the mammal brain and body
Increase IP3 and calcium by
activating phospholipase C.
Decrease cAMP by
inhibiting adenylate cyclase.
Increase cAMP by
activating adenylate cyclase.
Like many other biologically active substances, norepinephrine exerts
its effects by binding to and activating receptors located on the
surface of cells. Two broad families of norepinephrine receptors have
been identified, known as alpha and beta adrenergic receptors.
Alpha receptors are divided into subtypes α1 and α2; beta receptors
into subtypes β1, β2, and β3. All of these function as G
protein-coupled receptors, meaning that they exert their effects via a
complex second messenger system. Alpha-2 receptors usually have
inhibitory effects, but many are located pre-synaptically (i.e., on
the surface of the cells that release norepinephrine), so the net
effect of alpha-2 activation is often a decrease in the amount of
norepinephrine released. Alpha-1 receptors and all three types of
beta receptors usually have excitatory effects.
Storage, release, and reuptake
Norepinephrine (labeled "noradrenaline" in this drawing) processing in
a synapse. After release norepinephrine can either be taken up again
by the presynaptic terminal, or broken down by enzymes.
Inside the brain norepinephrine functions as a neurotransmitter, and
is controlled by a set of mechanisms common to all monoamine
neurotransmitters. After synthesis, norepinephrine is transported from
the cytosol into synaptic vesicles by the vesicular monoamine
Norepinephrine is stored in these vesicles
until it is ejected into the synaptic cleft, typically after an action
potential causes the vesicles to release their contents directly into
the synaptic cleft through a process called exocytosis.
Once in the synapse, norepinephrine binds to and activates receptors.
After an action potential, the norepinephrine molecules quickly become
unbound from their receptors. They are then absorbed back into the
presynaptic cell, via reuptake mediated primarily by the
norepinephrine transporter (NET). Once back in the cytosol,
norepinephrine can either be broken down by monoamine oxidase or
repackaged into vesicles by VMAT, making it available for future
Sympathetic nervous system
Main article: Sympathetic nervous system
Schema of the sympathetic nervous system, showing the sympathetic
ganglia and the parts of the body to which they connect.
Norepinephrine is the main neurotransmitter used by the sympathetic
nervous system, which consists of about two dozen sympathetic chain
ganglia located next to the spinal cord, plus a set of prevertebral
ganglia located in the chest and abdomen. These sympathetic
ganglia are connected to numerous organs, including the eyes, salivary
glands, heart, lungs, liver, gallbladder, stomach, intestines,
kidneys, urinary bladder, reproductive organs, muscles, skin, and
adrenal glands. Sympathetic activation of the adrenal glands
causes the part called the adrenal medulla to release norepinephrine
(as well as epinephrine) into the bloodstream, from which, functioning
as a hormone, it gains further access to a wide variety of
Broadly speaking, the effect of norepinephrine on each target organ is
to modify its state in a way that makes it more conducive to active
body movement, often at a cost of increased energy use and increased
wear and tear. This can be contrasted with the
acetylcholine-mediated effects of the parasympathetic nervous system,
which modifies most of the same organs into a state more conducive to
rest, recovery, and digestion of food, and usually less costly in
terms of energy expenditure.
The sympathetic effects of norepinephrine include:
In the eyes, an increase in production of tears, making the eyes more
moist., and pupil dilation through contraction of the iris
In the heart, an increase in the amount of blood pumped.
In brown adipose tissue, an increase in calories burned to generate
Multiple effects on the immune system. The sympathetic nervous system
is the primary path of interaction between the immune system and the
brain, and several components receive sympathetic inputs, including
the thymus, spleen, and lymph nodes. However the effects are complex,
with some immune processes activated while others are inhibited.
In the arteries, constriction of blood vessels, causing an increase in
In the kidneys, release of renin and retention of sodium in the
In the liver, an increase in production of glucose, either by
glycogenolysis after a meal or by gluconeogenesis when food has not
recently been consumed.
Glucose is the body's main energy source
in most conditions.
In the pancreas, increased release of glucagon, a hormone whose main
effect is to increase the production of glucose by the liver.
In skeletal muscles, an increase in glucose uptake.
In adipose tissue (i. e., fat cells), an increase in lipolysis, that
is, conversion of fat to substances that can be used directly as
energy sources by muscles and other tissues.
In the stomach and intestines, a reduction in digestive activity. This
results from a generally inhibitory effect of norepinephrine on the
enteric nervous system, causing decreases in gastrointestinal
mobility, blood flow, and secretion of digestive substances.
Central nervous system
Brain areas containing noradrenergic neurons.
The noradrenergic neurons in the brain form a neurotransmitter system,
that, when activated, exerts effects on large areas of the brain. The
effects are manifested in alertness, arousal, and readiness for
Noradrenergic neurons (i.e., neurons whose primary neurotransmitter is
norepinephrine) are comparatively few in number, and their cell bodies
are confined to a few relatively small brain areas, but they send
projections to many other brain areas and exert powerful effects on
their targets. These noradrenergic cell groups were first mapped in
1964 by Annica Dahlström and Kjell Fuxe, who assigned them labels
starting with the letter "A" (for "aminergic"). In their scheme,
areas A1 through A7 contain the neurotransmitter norepinephrine (A8
through A14 contain dopamine).
Noradrenergic cell group A1 is located
in the caudal ventrolateral part of the medulla, and plays a role in
the control of body fluid metabolism.
Noradrenergic cell group A2
is located in a brainstem area called the solitary nucleus; these
cells have been implicated in a variety of responses, including
control of food intake and responses to stress. Cell groups A5 and
A7 project mainly to the spinal cord.
The most important source of norepinephrine in the brain is the locus
coeruleus, which contains noradrenergic cell group A6 and adjoins cell
group A4. The locus coeruleus is quite small in absolute terms—in
primates it is estimated to contain around 15,000 neurons, less than
one millionth of the neurons in the brain—but it sends projections
to every major part of the brain and also to the spinal cord.
The level of activity in the locus coeruleus correlates broadly with
vigilance and speed of reaction. LC activity is low during sleep and
drops to virtually nothing during the REM (dreaming) state. It
runs at a baseline level during wakefulness, but increases temporarily
when a person is presented with any sort of stimulus that draws
attention. Unpleasant stimuli such as pain, difficulty breathing,
bladder distension, heat or cold generate larger increases. Extremely
unpleasant states such as intense fear or intense pain are associated
with very high levels of LC activity.
Norepinephrine released by the locus coeruleus affects brain function
in a number of ways. It enhances processing of sensory inputs,
enhances attention, enhances formation and retrieval of both long term
and working memory, and enhances the ability of the brain to respond
to inputs by changing the activity pattern in the prefrontal cortex
and other areas. The control of arousal level is strong enough
that drug-induced suppression of the LC has a powerful sedating
There is great similarity between situations that activate the locus
coeruleus in the brain and situations that activate the sympathetic
nervous system in the periphery: the LC essentially mobilizes the
brain for action while the sympathetic system mobilizes the body. It
has been argued that this similarity arises because both are to a
large degree controlled by the same brain structures, particularly a
part of the brainstem called the nucleus gigantocellularis.
A large number of important drugs exert their effects by interacting
with norepinephrine systems in the brain or body. Their uses include
treatment of cardiovascular problems, shock, and a variety of
psychiatric conditions. These drugs are divided into: sympathomimetic
drugs which mimic or enhance at least some of the effects of
norepinephrine released by the sympathetic nervous system;
sympatholytic drugs, in contrast, block at least some of the
effects. Both of these are large groups with diverse uses,
depending on exactly which effects are enhanced or blocked.
Norepinephrine itself is classified as a sympathomimetic drug: its
effects when given by intravenous injection of increasing heart rate
and force and constricting blood vessels make it very useful for
treating medical emergencies that involve critically low blood
Surviving Sepsis Campaign
Surviving Sepsis Campaign recommended norepinephrine as
first line agent in treating septic shock which is unresponsive to
fluid resuscitation, supplemented by vasopressin and epinephrine.
Dopamine usage is restricted only to highly selected patients.
Main article: Beta blocker
These are sympatholytic drugs that block the effects of beta
adrenergic receptors while having little or no effect on alpha
receptors. They are sometimes used to treat high blood pressure,
atrial fibrillation and congestive heart failure, but recent reviews
have concluded that other types of drugs are usually superior for
those purposes. Beta blockers may be a viable choice for other
cardiovascular conditions, though, including angina and Marfan
syndrome. They are also widely used to treat glaucoma, most
commonly in the form of eyedrops. Because of their effects in
reducing anxiety symptoms and tremor, they have sometimes been used by
entertainers, public speakers and athletes to reduce performance
anxiety, although they are not medically approved for that purpose and
are banned by the International Olympic Committee.
However, the usefulness of beta blockers is limited by a range of
serious side effects, including slowing of heart rate, a drop in blood
pressure, asthma, and reactive hypoglycemia. The negative effects
can be particularly severe in people who suffer from diabetes.
Main article: Alpha blocker
These are sympatholytic drugs that block the effects of adrenergic
alpha receptors while having little or no effect on beta
receptors. Drugs belonging to this group can have very different
effects, however, depending on whether they primarily block alpha-1
receptors, alpha-2 receptors, or both. Alpha-2 receptors, as described
elsewhere in this article, are frequently located on
norepinephrine-releasing neurons themselves and have inhibitory
effects on them; consequently blockage of alpha-2 receptors usually
results in an increase in norepinephrine release. Alpha-1
receptors are usually located on target cells and have excitatory
effects on them; consequently blockage of alpha-1 receptors usually
results in blocking some of the effects of norepinephrine. Drugs
such as phentolamine that act on both types of receptors can produce a
complex combination of both effects. In most cases when the term
"alpha blocker" is used without qualification, it refers to a
selective alpha-1 antagonist.
Selective alpha-1 blockers have a variety of uses. Because one of
their effects is to relax the muscles in the neck of the bladder, they
are often used to treat benign prostatic hyperplasia, and to help with
the expulsion of bladder stones. Their effects on the central
nervous system make them useful for treating generalized anxiety
disorder, panic disorder, and posttraumatic stress disorder. They
may, however, have significant side-effects, including a drop in blood
Some antidepressants function partly as selective alpha-2 blockers,
but the best-known drug in that class is yohimbine, which is extracted
from the bark of the African yohimbe tree.
Yohimbine acts as a
male potency enhancer, but its usefulness for that purpose is limited
by serious side-effects including anxiety and insomnia. Overdoses
can cause a dangerous increase in blood pressure.
banned in many countries, but in the United States, because it is
extracted from a plant rather than chemically synthesized, it is sold
over the counter as a nutritional supplement.
These are sympathomimetic drugs that activate alpha-2 receptors or
enhance their effects. Because alpha-2 receptors are inhibitory and
many are located presynaptically on norepinephrine-releasing cells,
the net effect of these drugs is usually to reduce the amount of
norepinephrine released. Drugs in this group that are capable of
entering the brain often have strong sedating effects, due to their
inhibitory effects on the locus coeruleus. Clonidine, for example,
is used for the treatment of anxiety disorders and insomnia, and also
as a sedative premedication for patients about to undergo surgery.
Xylazine, another drug in this group, is also a powerful sedative and
is often used in combination with ketamine as a general anaesthetic
for veterinary surgery—in the United States it has not been approved
for use in humans.
Stimulants and antidepressants
Stimulant § Mechanisms of action, and Antidepressant
These are drugs whose primary effects are thought to be mediated by
different neurotransmitter systems (dopamine for stimulants, serotonin
for antidepressants), but many also increase levels of norepinephrine
in the brain. Amphetamine, for example, is a
stimulant that increases release of norepinephrine as well as
Monoamine oxidase inhibitors are antidepressants that
inhibit the metabolic degradation of norepinephrine as well as
serotonin. In some cases it is difficult to
distinguish the norepinephrine-mediated effects from the effects
related to other neurotransmitters.
Diseases and disorders
A number of important medical problems involve dysfunction of the
norepinephrine system in the brain or body.
Hyperactivation of the sympathetic nervous system is not a recognized
condition in itself, but it is a component of a number of conditions,
as well as a possible consequence of taking sympathomimetic drugs. It
causes a distinctive set of symptoms including aches and pains, rapid
heartbeat, elevated blood pressure, sweating, palpitations, anxiety,
headache, paleness, and a drop in blood glucose. If sympathetic
activity is elevated for an extended time, it can cause weight loss
and other stress-related body changes.
The list of conditions that can cause sympathetic hyperactivation
includes severe brain injury, spinal cord damage, heart
failure, high blood pressure, kidney disease, and various
types of stress.
A pheochromocytoma is a rarely occurring tumor of the adrenal medulla,
caused either by genetic factors or certain types of cancer. The
consequence is a massive increase in the amount of norepinephrine and
epinephrine released into the bloodstream. The most obvious symptoms
are those of sympathetic hyperactivation, including particularly a
rise in blood pressure that can reach fatal levels. The most effective
treatment is surgical removal of the tumor.
Stress, to a physiologist, means any situation that threatens the
continued stability of the body and its functions. Stress affects
a wide variety of body systems: the two most consistently activated
are the hypothalamic-pituitary-adrenal axis and the norepinephrine
system, including both the sympathetic nervous system and the locus
coeruleus-centered system in the brain. Stressors of many types
evoke increases in noradrenergic activity, which mobilizes the brain
and body to meet the threat. Chronic stress, if continued for a
long time, can damage many parts of the body. A significant part of
the damage is due to the effects of sustained norepinephrine release,
because of norepinephrine's general function of directing resources
away from maintenance, regeneration, and reproduction, and toward
systems that are required for active movement. The consequences can
include slowing of growth (in children), sleeplessness, loss of
libido, gastrointestinal problems, impaired disease resistance, slower
rates of injury healing, depression, and increased vulnerability to
Attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder is a psychiatric condition
involving problems with attention, hyperactivity, and
impulsiveness. It is most commonly treated using stimulant drugs
such as methylphenidate (Ritalin), whose primary effect is to increase
dopamine levels in the brain, but drugs in this group also generally
increase brain levels of norepinephrine, and it has been difficult to
determine whether these actions are involved in their clinical value.
Also there is substantial evidence that many people with ADHD show
"biomarkers" involving altered norepinephrine processing. Several
drugs whose primary effects are on norepinephrine, including
guanfacine, clonidine, and atomoxetine, have been tried as treatments
for ADHD, and found to have effects comparable to those of
Several conditions, including Parkinson's disease, diabetes and
so-called pure autonomic failure, can cause a loss of
norepinephrine-secreting neurons in the sympathetic nervous system.
The symptoms are widespread, the most serious being a reduction in
heart rate and an extreme drop in resting blood pressure, making it
impossible for severely affected people to stand for more than a few
seconds without fainting. Treatment can involve dietary changes or
Comparative biology and evolution
Chemical structure of octopamine, which serves as the homologue of
norepinephrine in many invertebrate species
Norepinephrine has been reported to exist in a wide variety of animal
species, including protozoa, placozoa and cnidaria (jellyfish and
related species), but not in ctenophores (comb jellies), whose
nervous systems differ greatly from those of other animals. It is
generally present in deuterostomes (vertebrates, etc.), but in
protostomes (arthropods, molluscs, flatworms, nematodes, annelids,
etc.) it is replaced by octopamine, a closely related chemical with a
closely related synthesis pathway. In insects, octopamine has
alerting and activating functions that correspond (at least roughly)
with the functions of norepinephrine in vertebrates. It has been
argued that octopamine evolved to replace norepinephrine rather than
vice versa; however, the nervous system of amphioxus (a primitive
chordate) has been reported to contain octopamine but not
norepinephrine, which presents difficulties for that hypothesis.
Main article: History of catecholamine research
Early in the twentieth century Walter Cannon, who had popularized the
idea of a sympathoadrenal system preparing the body for fight and
flight, and his colleague
Arturo Rosenblueth developed a theory of two
sympathins, sympathin E (excitatory) and sympathin I (inhibitory),
responsible for these actions. The Belgian pharmacologist Zénon
Bacq as well as Canadian and US-American pharmacologists between 1934
and 1938 suggested that noradrenaline might be a sympathetic
transmitter. In 1939, Hermann Blaschko and Peter Holtz
independently identified the biosynthetic mechanism for norepinephrine
in the vertebrate body. In 1945
Ulf von Euler
Ulf von Euler published the
first of a series of papers that established the role of
norepinephrine as a neurotransmitter. He demonstrated the presence
of norepinephrine in sympathetically innervated tissues and brain, and
adduced evidence that it is the sympathin of Cannon and Rosenblueth.
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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)
activin and inhibin
Insulin-like growth factor
Adrenergic receptor modulators
Atypical antipsychotics (e.g., brexpiprazole, clozapine, olanzapine,
Ergolines (e.g., ergotamine, dihydroergotamine, lisuride, terguride)
Phenylpiperazine antidepressants (e.g., hydroxynefazodone, nefazodone,
Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin)
Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin,
Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine,
Atypical antipsychotics (e.g., asenapine, brexpiprazole, clozapine,
lurasidone, paliperidone, quetiapine, risperidone, zotepine)
Azapirones (e.g., buspirone, gepirone, ipsapirone, tandospirone)
Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine,
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
Amphetamine (Dextroamphetamine, Levoamphetamine)
Fenfluramine (Dexfenfluramine, Levofenfluramine)
Methamphetamine (Dextromethamphetamine, Levomethamphetamine)
Selegiline (also D -Deprenyl)
(and close relatives)
D -DOPA (Dextrodopa)
L -DOPA (Levodopa)
L -DOPS (Droxidopa)
Lysergic acid amide
Lysergic acid 2-butyl amide
Lysergic acid 2,4-dimethylazetidide
Lysergic acid diethylamide