Norepinephrine

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This article is about the hormone and neurotransmitter. For the medication used in treating low blood pressure, see norepinephrine (medication).

Norepinephrine
COMT
Identifiers
  • (R)-4-(2-amino-1-hydroxyethyl)benzene-1,2-diol
JSmol)
  • NC[C@H](O)c1cc(O)c(O)cc1
  • InChI=1S/C8H11NO3/c9-4-8(12)5-1-2-6(10)7(11)3-5/h1-3,8,10-12H,4,9H2/t8-/m0/s1
  • Key:SFLSHLFXELFNJZ-QMMMGPOBSA-N

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an

drug.[3]
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.

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

gastrointestinal motility
.

In the brain, noradrenaline is produced in

Merkel cells located in the skin. 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 adrenergic receptors
located on the cell surface.

A variety of medically important drugs work by altering the actions of noradrenaline systems.

ADHD
. Many important psychiatric drugs exert strong effects on noradrenaline systems in the brain, resulting in side-effects that may be helpful or harmful.

Structure

Norepinephrine is a

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.[4] The prefix nor- is derived as an abbreviation of the word "normal", used to indicate a demethylated compound.[5] Norepinephrine consists of a catechol moiety (a benzene ring with two adjoining hydroxyl groups in the meta-para position), and an ethylamine side chain consisting of a hydroxyl group bonded in the benzylic position.[6][7]

Chemical diagram of the structure of a norepinephrine molecule.
Norepinephrine structure
Chemical diagram of the structure of an epinephrine molecule
Epinephrine structure
Chemical diagram of a catechol structure.
Catechol structure

Biochemical mechanisms

Biosynthesis

Biosynthetic pathways for catecholamines and trace amines in the human brain[8][9][10]
The image above contains clickable links
Norepinephrine is synthesized from dopamine in the human body by the
dopamine β-hydroxylase (DBH) enzyme
.

Norepinephrine is

dopamine β-monooxygenase occurs predominantly inside neurotransmitter vesicles.[11] The metabolic pathway
is:

Phenylalanine → Tyrosine → L-DOPA → Dopamine → Norepinephrine[11]

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.[11] 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

ascorbic acid as cofactors.[11]

Norepinephrine itself can further be converted into

epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as cofactor.[11]

Degradation

In mammals, norepinephrine is rapidly degraded to various

MHPG, both of which are thought to be biologically inactive and are excreted in the urine.[13]

Norepinephrine degradation.[13] Metabolizing enzymes are shown in boxes.

Functions

Cellular effects

Main article: Adrenergic receptor
Adrenergic receptors in the mammal brain and body[13]
Family Receptor Type Mechanism
Alpha
 α1 Gq-coupled. Increase IP3 and calcium by
activating phospholipase C.
α2 Gi/Go-coupled. Decrease
adenylate cyclase
.
Beta
 β1 Gs-coupled. Increase
adenylate cyclase
.
β2
β3

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.[13] Alpha receptors are divided into subtypes α1 and α2; beta receptors into subtypes β1, β2, and β3.[13] All of these function as G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system.[13] 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.[13] Alpha-1 receptors and all three types of beta receptors usually have excitatory effects.[13]

Storage, release, and reuptake

Cartoon diagram of a noradrenergic synapse, showing the synthetic and metabolic mechanisms as well as the things that can happen after release.
Norepinephrine (labeled "noradrénaline" 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

neuromodulator, and is controlled by a set of mechanisms common to all monoamine neurotransmitters.[14] After synthesis, norepinephrine is transported from the cytosol into synaptic vesicles by the vesicular monoamine transporter (VMAT).[15] VMAT can be inhibited by Reserpine causing a decrease in neurotransmitter stores. 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.[13]

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).[16] 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 release.[15]

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.[17] 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.[17] 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 tissues.[17]

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.[18] 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.[18]

The sympathetic effects of norepinephrine include:

  • In the eyes, an increase in production of tears, making the eyes more moist,
    iris dilator
    .
  • In the heart, an increase in the amount of blood pumped.[20]
  • In brown adipose tissue, an increase in calories burned to generate body heat (thermogenesis).[21]
  • 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.[22]
  • In the arteries, constriction of blood vessels, causing an increase in blood pressure.[23]
  • In the
    kidneys, release of renin and retention of sodium in the bloodstream.[24]
  • 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.[24] 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.[24]
  • In skeletal muscles, an increase in glucose uptake.[24]
  • 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.[24]
  • 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.[25]

Noradrenaline and

CB1 receptors mediate the sympatho-inhibitory action. Thus cannabinoids can inhibit both the noradrenergic and purinergic components of sympathetic neurotransmission.[26]

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 action.

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").[27] 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.[28] 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.[29] Cell groups A5 and A7 project mainly to the spinal cord.[30]

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.[31]

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.[32] 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.[31]

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.[33] The control of arousal level is strong enough that drug-induced suppression of the LC has a powerful sedating effect.[32]

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.[31]

Skin

Norepinephrine is also produced by Merkel cells which are part of the somatosensory system. It activates the afferent sensory neuron.[34]

Pharmacology

See also: Norepinephrine (medication)

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.[35] Both of these are large groups with diverse uses, depending on exactly which effects are enhanced or blocked.[35]

epinephrine. Dopamine usage is restricted only to highly selected patients.[36]

Antagonists

Beta blockers

Main article: Beta blocker

These are

performance anxiety, although they are not medically approved for that purpose and are banned by the International Olympic Committee.[41][42]

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.[40] The negative effects can be particularly severe in people with diabetes.[37]

Alpha blockers

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.[43] 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.[43] 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.[43] 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

posttraumatic stress disorder.[46] They may, however, have significant side-effects, including a drop in blood pressure.[43]

Some antidepressants function partly as selective

nutritional supplement.[48]

Alpha-2 agonists

These are

alpha-2 receptors or enhance their effects.[49] 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.[49] 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.[49] clonidine and guanfacine, for example, are used for the treatment of anxiety disorders and insomnia, and also as a sedative premedication for patients about to undergo surgery.[50] 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.[51]

Stimulants and antidepressants

See also: Stimulant § Mechanisms of action, and Antidepressant § Pharmacology

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.[52] Amphetamine, for example, is a stimulant that increases release of norepinephrine as well as dopamine.[53] Monoamine oxidase A inhibitors (MAO-A) are antidepressants that inhibit the metabolic degradation of norepinephrine as well as serotonin and dopamine.[54] In some cases it is difficult to distinguish the norepinephrine-mediated effects from the effects related to other neurotransmitters.[citation needed]

Diseases and disorders

A number of important medical problems involve dysfunction of the norepinephrine system in the brain or body.

Sympathetic hyperactivation

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,[55] spinal cord damage,[56] heart failure,[57] high blood pressure,[58] kidney disease,[59] and various types of stress.

Pheochromocytoma

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

hypothalamic-pituitary-adrenal axis and the norepinephrine system, including both the sympathetic nervous system and the locus coeruleus-centered system in the brain.[60] Stressors of many types evoke increases in noradrenergic activity, which mobilizes the brain and body to meet the threat.[60] 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 addiction.[60]

ADHD

Attention deficit hyperactivity disorder is a neurodevelopmental condition involving problems with attention, hyperactivity, and impulsiveness.[61] 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. There is also substantial evidence that many people with ADHD show biomarkers involving altered norepinephrine processing.[62] 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 stimulants.[63][64]

Autonomic failure

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 drugs.[65]

REM sleep deprivation

Norepiprephine prevents REM sleep, and lack of REM sleep increases noradrenaline secretion[66] as a result of the locus coeruleus not ceasing producing it. It causes neurodegeneration if its loss is sustained for several days.[67]

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

amphioxus (a primitive chordate) has been reported to contain octopamine but not norepinephrine, which presents difficulties for that hypothesis.[68]

History

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.[72] The Belgian pharmacologist Zénon Bacq as well as Canadian and U.S. pharmacologists between 1934 and 1938 suggested that noradrenaline might be a sympathetic transmitter.[72] In 1939, Hermann Blaschko and Peter Holtz independently identified the biosynthetic mechanism for norepinephrine in the vertebrate body.[73][74] In 1945 Ulf von Euler published the first of a series of papers that established the role of norepinephrine as a neurotransmitter.[75] He demonstrated the presence of norepinephrine in sympathetically innervated tissues and brain, and adduced evidence that it is the sympathin of Cannon and Rosenblueth.

Stanley Peart was the first to demonstrate the release of noradrenaline after the stimulation of sympathetic nerves.

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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Norepinephrine&oldid=1214480706"