Norepinephrine (NE), also callednoradrenaline (NA) ornoradrenalin, is anorganic chemical in thecatecholamine family that functions in thebrain andbody as ahormone,neurotransmitter andneuromodulator. The name "noradrenaline" (fromLatinad, "near", andren, "kidney") is more commonly used in the United Kingdom and the rest of the world, whereas "norepinephrine" (fromAncient Greekἐπῐ́ (epí), "upon", andνεφρός (nephrós), "kidney") is usually preferred in the United States.[2] "Norepinephrine" is also theinternational nonproprietary name given to thedrug.[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 asnoradrenergic.
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-calledfight-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 increasesheart rate andblood pressure, triggers the release ofglucose from energy stores, increasesblood flow toskeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder andgastrointestinal motility.
In the brain, noradrenaline is produced innuclei that are small yet exert powerful effects on other brain areas. The most important of these nuclei is thelocus coeruleus, located in thepons. Outside the brain, norepinephrine is used as a neurotransmitter bysympathetic ganglia located near thespinal cord or in theabdomen, as well asMerkel cells located in the skin. It is also released directly into the bloodstream by theadrenal glands. Regardless of how and where it is released, norepinephrine acts on target cells by binding to and activatingadrenergic receptors located on the cell surface.
A variety of medically important drugs work by altering the actions of noradrenaline systems.Noradrenaline itself is widely used as an injectable drug for the treatment of critically low blood pressure.Stimulants often increase, enhance, or otherwise act asagonists of norepinephrine. Drugs such ascocaine andmethylphenidate act asreuptake inhibitors of norepinephrine, as do someantidepressants, such as those in theSNRI class. One of the more notable drugs in the stimulant class isamphetamine, which acts as a dopamine and norepinephrine analog, reuptake inhibitor, as well as an agent that increases the amount of globalcatecholamine signaling throughout the nervous system by reversing transporters in thesynapses.Beta blockers, which counter some of the effects of noradrenaline by blocking beta-adrenergic receptors, are sometimes used to treat glaucoma, migraines and a range of cardiovascular diseases. β1Rs preferentially bind epinephrine, along with norepinephrine to a lesser extent and mediates some of their cellular effects in cardiac myocytes such as increased positive inotropy and lusitropy. β-blockers exert their cardioprotective effects through decreasing oxygen demand in cardiac myocytes; this is accomplished via decreasing the force of contraction during systole (negative inotropy) and decreasing the rate of relaxation during diastole (negative lusitropy), thus reducing myocardial energy demand which is useful in treating cardiovascular disorders accompanied by inadequate myocardial oxygen supply.Alpha blockers, which counter the effects of noradrenaline on alpha-adrenergic receptors, are occasionally used to treat hypertension and psychiatric conditions.Alpha-2 agonists often have a sedating and antihypertensive effect and are commonly used as anesthesia enhancers in surgery, as well as in treatment of drug oralcohol dependence. For reasons that are still unclear, some Alpha-2 agonists, such asguanfacine, have also been shown to be effective in the treatment of anxiety disorders andADHD. Many important psychiatric drugs exert strong effects on noradrenaline systems in the brain, resulting in effects that may be helpful or harmful.
Norepinephrine is acatecholamine and aphenethylamine.[4] Its structure differs from that ofepinephrine only in that epinephrine has amethyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine.[4] The prefixnor- is derived as an abbreviation of the word "normal", used to indicate ademethylated compound.[5] Norepinephrine consists of a catechol moiety (a benzene ring with two adjoining hydroxyl groups in themeta-para position), and an ethylamine side chain consisting of a hydroxyl group bonded in the benzylic position.[6][7]
Thus the direct precursor of norepinephrine isdopamine, which is synthesized indirectly from the essential amino acidphenylalanine or the non-essential amino acidtyrosine.[12] 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.
In mammals, norepinephrine is rapidly degraded to variousmetabolites. The initial step in the breakdown can be catalyzed by either of the enzymesmonoamine oxidase (mainlymonoamine oxidase A) orCOMT.[13] From there, the breakdown can proceed by a variety of pathways. The principal end products are eitherVanillylmandelic acid or a conjugated form ofMHPG, both of which are thought to be biologically inactive and are excreted in the urine.[14]
Norepinephrine degradation.[14] Metabolizing enzymes are shown in boxes.
Like many other biologically active substances, norepinephrine exerts its effects by binding to and activatingreceptors located on the surface of cells. Two broad families of norepinephrine receptors have been identified, known as alpha and beta-adrenergic receptors.[14] Alpha receptors are divided into subtypesα1 andα2; beta receptors into subtypesβ1,β2, andβ3.[14] All of these function asG protein-coupled receptors, meaning that they exert their effects via a complexsecond messenger system.[14] 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.[14] Alpha-1 receptors and all three types of beta receptors usually have excitatory effects.[14]
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.
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, viareuptake mediated primarily by thenorepinephrine transporter (NET).[17] Once back in the cytosol, norepinephrine can either be broken down bymonoamine oxidase or repackaged into vesicles by VMAT, making it available for future release.[16]
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 dozensympathetic chain ganglia located next to the spinal cord, plus a set ofprevertebral ganglia located in the chest and abdomen.[18] 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.[18] Sympathetic activation of the adrenal glands causes the part called theadrenal medulla to release norepinephrine (as well as epinephrine) into the bloodstream, from which, functioning as ahormone, it gains further access to a wide variety of tissues.[18]
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.[19] This can be contrasted with theacetylcholine-mediated effects of theparasympathetic 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.[19]
The sympathetic effects of norepinephrine include:
In the eyes, an increase in the production of tears, making the eyes more moist,[20] andpupil dilation through contraction of theiris dilator.
In the heart, an increase in the amount of blood pumped.[21]
Multiple effects on theimmune 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 thethymus,spleen, andlymph nodes. However, the effects are complex, with some immune processes activated while others are inhibited.[23]
In thearteries, constriction of blood vessels causes an increase in blood pressure.[24]
In thekidneys, release ofrenin and retention of sodium in the bloodstream.[25]
In theliver, an increase in production ofglucose, either byglycogenolysis after a meal or bygluconeogenesis when food has not recently been consumed.[25] Glucose is the body's main energy source in most conditions.
In thepancreas, increased release ofglucagon, a hormone whose main effect is to increase the production of glucose by the liver.[25]
In skeletal muscles, an increase in glucose uptake.[25]
Inadipose tissue (i.e., fat cells), an increase inlipolysis, that is, conversion of fat to substances that can be used directly as energy sources by muscles and other tissues.[25]
In thestomach and intestines, a reduction in digestive activity. This results from a generally inhibitory effect of norepinephrine on theenteric nervous system, causing decreases in gastrointestinal mobility, blood flow, and secretion of digestive substances.[26]
The noradrenergic neurons in the brain form aneurotransmitter 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. Thesenoradrenergic cell groups were first mapped in 1964 by Annica Dahlström and Kjell Fuxe, who assigned them labels starting with the letter "A" (for "aminergic").[28] In their scheme, areas A1 through A7 contain the neurotransmitter norepinephrine (A8 through A14 containdopamine).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.[29]Noradrenergic cell group A2 is located in a brainstem area called thesolitary nucleus; these cells have been implicated in a variety of responses, including control of food intake and responses to stress.[30] Cell groupsA5 andA7 project mainly to the spinal cord.[31]
The most important source of norepinephrine in the brain is thelocus coeruleus, which containsnoradrenergic cell group A6 and adjoins cell groupA4. 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.[32]
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.[33] 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.[32]
Norepinephrine released by the locus coeruleus affects brain function in several 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.[34] The control of arousal level is strong enough that drug-induced suppression of the LC has a powerful sedating effect.[33]
There is a 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 thenucleus gigantocellularis.[32]
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.[36] Both of these are large groups with diverse uses, depending on exactly which effects are enhanced or blocked.[36]
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 pressure.[36]Surviving Sepsis Campaign recommended norepinephrine as first line agent in treatingseptic shock which is unresponsive tofluid resuscitation, supplemented byvasopressin andepinephrine.Dopamine usage is restricted only to highly selected patients.[37]
These aresympatholytic drugs that block the effects ofbeta adrenergic receptors while having little or no effect on alpha receptors. They are sometimes used to treathigh blood pressure,atrial fibrillation, andcongestive heart failure, but recent reviews have concluded that other types of drugs are usually superior for those purposes.[38][39] Beta blockers may be a viable choice for other cardiovascular conditions, though, includingangina andMarfan syndrome.[40] They are also widely used to treatglaucoma, most commonly in the form of eyedrops.[41] Because of their effects in reducing anxiety symptoms and tremor, they have sometimes been used by entertainers, public speakers, and athletes to reduceperformance anxiety, although they are not medically approved for that purpose and are banned by theInternational Olympic Committee.[42][43]
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, andreactive hypoglycemia.[41] The negative effects can be particularly severe in people withdiabetes.[38]
These aresympatholytic drugs that block the effects of adrenergic alpha receptors while having little or no effect on beta receptors.[44] 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.[44] 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.[44] Drugs such asphentolamine 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.
Selectivealpha-1 blockers have a variety of uses. Since one of their effects is to inhibit the contraction of the smooth muscle in the prostate, they are often used to treat symptoms ofbenign prostatic hyperplasia.[45] Alpha-blockers also likely help people pass their kidney stones.[46] Their effects on the central nervous system make them useful for treatinggeneralized anxiety disorder,panic disorder, andposttraumatic stress disorder.[47] They may, however, have significant side effects, including a drop in blood pressure.[44]
Some antidepressants function partly as selectivealpha-2 blockers, but the best-known drug in that class isyohimbine, which is extracted from the bark of the Africanyohimbe tree.[48] Yohimbine acts as amale potency enhancer, but its usefulness for that purpose is limited by serious side-effects including anxiety and insomnia.[48] Overdoses can cause a dangerous increase in blood pressure.[48] Yohimbine is banned in many countries, but in the United States, because it is extracted from a plant rather than chemically synthesized, it is soldover the counter as anutritional supplement.[49]
These aresympathomimetic drugs that activatealpha-2 receptors or enhance their effects.[50] 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.[50] Drugs in this group that are capable of entering the brain often have strong sedating effects, due to their inhibitory effects on thelocus coeruleus.[50]Clonidine andguanfacine, for example, are used for the treatment of anxiety disorders and insomnia, and also as a sedativepremedication for patients about to undergo surgery.[51]Xylazine, another drug in this group, is also a powerful sedative and is often used in combination withketamine as ageneral anaesthetic forveterinary surgery—in the United States it has not been approved for use in humans.[52]
These are drugs whose primary effects are thought to be mediated by different neurotransmitter systems (dopamine forstimulants,serotonin forantidepressants), but many also increase levels of norepinephrine in the brain.[53]Amphetamine, for example, is a stimulant that increases release of norepinephrine as well as dopamine.[54]Monoamine oxidase A inhibitors (MAO-A) are antidepressants that inhibit the metabolic degradation of norepinephrine as well as serotonin and dopamine.[55] In some cases it is difficult to distinguish the norepinephrine-mediated effects from the effects related to other neurotransmitters.[citation needed]
Hyperactivation of thesympathetic 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 takingsympathomimetic 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,[56] spinal cord damage,[57] heart failure,[58] high blood pressure,[59] kidney disease,[60] and various types of stress.
Apheochromocytoma is a rarely occurring tumor of theadrenal 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.[61] Stress affects a wide variety of body systems: the two most consistently activated are thehypothalamic-pituitary-adrenal axis and the norepinephrine system, including both thesympathetic nervous system and thelocus coeruleus-centered system in the brain.[61] Stressors of many types evoke increases in noradrenergic activity, which mobilizes the brain and body to meet the threat.[61] 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.[61]
Attention deficit hyperactivity disorder is a neurodevelopmental condition involving problems with attention, hyperactivity, and impulsiveness.[62] It is most commonly treated usingstimulant drugs such asmethylphenidate (Ritalin), whose primary effect is to increasedopamine 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 showbiomarkers involving altered norepinephrine processing.[63] Several drugs whose primary effects are on norepinephrine, includingguanfacine,clonidine, andatomoxetine, have been tried as treatments for ADHD, and found to have effects comparable to those of stimulants.[64][65]
Several conditions, includingParkinson's disease,diabetes, and so-calledpure 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.[66]
Norepinephrine preventsREM sleep, and lack of REM sleep increases noradrenaline secretion[67] as a result of the locus coeruleus not ceasing producing it. It causes neurodegeneration if its loss is sustained for several days.[68]
Chemical structure ofoctopamine, which serves as thehomologue of norepinephrine in many invertebrate species
Norepinephrine has been reported to exist in a wide variety of animal species, includingprotozoa,[69]placozoa andcnidaria (jellyfish and related species),[70] but not inctenophores (comb jellies), whose nervous systems differ greatly from those of other animals.[71] It is generally present indeuterostomes (vertebrates, etc.), but inprotostomes (arthropods, molluscs, flatworms, nematodes, annelids, etc.) it is replaced byoctopamine, a closely related chemical with a closely related synthesis pathway.[69] In insects, octopamine has alerting and activating functions that correspond (at least roughly) with the functions of norepinephrine in vertebrates.[72] It has been argued that octopamine evolved to replace norepinephrine rather thanvice versa; however, the nervous system ofamphioxus (a primitive chordate) has been reported to contain octopamine but not norepinephrine, which presents difficulties for that hypothesis.[69]
Early in the twentieth centuryWalter Cannon, who had popularized the idea of asympathoadrenal system preparing the body forfight and flight, and his colleagueArturo Rosenblueth developed a theory of twosympathins,sympathin E (excitatory) andsympathin I (inhibitory), responsible for these actions.[73] The Belgian pharmacologistZénon Bacq as well as Canadian and U.S. pharmacologists between 1934 and 1938 suggested that noradrenaline might be a sympathetic transmitter.[73] In 1939, Hermann Blaschko and Peter Holtz independently identified the biosynthetic mechanism for norepinephrine in the vertebrate body.[74][75] In 1945Ulf von Euler published the first of a series of papers that established the role of norepinephrine as a neurotransmitter.[76] He demonstrated the presence of norepinephrine in sympathetically innervated tissues and brain, and adduced evidence that it is thesympathin 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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Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages.See also:Receptor/signaling modulators
