Norepinephrine

Norepinephrine is a catecholamine and a phenethylamine.{{cite web |url=https://pubchem.ncbi.nlm.nih.gov/compound/439260 |title=Norepinephrine |work=PubChem |access-date=6 November 2015}} 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 demethylated compound.{{cite journal | vauthors = Gaddum JH |title=The Prefix 'Nor' in Chemical Nomenclature |journal=Nature |volume=177 |issue=1046 |pages= 1046|date=June 1956 |doi=10.1038/1771046b0 |bibcode = 1956Natur.177.1046G |s2cid=4284979 |doi-access=free }} 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.{{cite journal | vauthors = Mittal R, Debs LH, Patel AP, Nguyen D, Patel K, O'Connor G, Grati M, Mittal J, Yan D, Eshraghi AA, Deo SK, Daunert S, Liu XZ | title = Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis | journal = Journal of Cellular Physiology | volume = 232 | issue = 9 | pages = 2359–2372 | date = September 2017 | pmid = 27512962 | pmc = 5772764 | doi = 10.1002/jcp.25518 }}{{Cite book | vauthors = Ritter J, Flower RJ, Henderson G, Loke YK, MacEwan DJ, Rang HP | title = Rang and Dale's pharmacology |publisher=Elsevier |date=2020 |isbn=978-0-7020-8060-9 |edition=Ninth |location=Edinburgh |oclc=1081403059}}

{{Catecholamine and trace amine biosynthesis|align=right|caption=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 norepinephrine that functions as a neurotransmitter in the brain is produced in the locus coeruleus, located in the pons of the brainstem.{{cite journal | vauthors = Bari BA, Chokshi V, Schmidt K | title = Locus coeruleus-norepinephrine: basic functions and insights into Parkinson's disease | journal = Neural Regeneration Research | volume = 15 | issue = 6 | pages = 1006–1013 | date = June 2020 | pmid = 31823870 | doi = 10.4103/1673-5374.270297 | doi-access = free | pmc = 7034292 }}

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 pathway is:

:Phenylalanine → Tyrosine → L-DOPA → Dopamine → Norepinephrine

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 cofactors. Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O₂, and probably ferrous iron (Fe²⁺) as cofactors.{{cite book |title=Biochemistry of Biogenic Amines |chapter=Chapter 1: Enzymes involved in the biosynthesis and degradation of catecholamines |url=https://books.google.com/books?id=BO7TBwAAQBAJ&pg=PA1 | vauthors= Musacchio JM | veditors = Iverson L |publisher=Springer |isbn=978-1-4684-3171-1 |year=2013 |pages=1–35}} Conversion of tyrosine to L-DOPA is inhibited by Metyrosine, a tyrosine analog. 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. Dopamine is 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.{{cite book | vauthors = Griffith RK | chapter = Chapter 10: Adrenergic Receptors and Drugs Affecting Adrenergic Neurotransmission | chapter-url = https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA343 | veditors = Lemke TL, Williams DA, Zito SW, Roche VF | title = Foye's Principles of Medicinal Chemistry | date = 2013 | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Philadelphia | isbn = 978-1-60913-345-0 | page = 343 | edition = 7th }} 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.{{cite book | chapter = Chapter 14: Noradrenergic transmission | vauthors = Rang HP, Ritter JM, Flower R, Henderson G | title = Rang & Dale's Pharmacology | publisher = Elsevier Health Sciences | year = 2014 | pages = 177–196 | isbn = 978-0-7020-5497-6 }}

File:Noradrenaline breakdown.svg

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{{Main|Adrenergic receptor}}

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.

File:Synapse noradrenergique1.png

Inside the brain norepinephrine functions as a neurotransmitter and neuromodulator, and is controlled by a set of mechanisms common to all monoamine neurotransmitters.{{cite journal |vauthors=O'Donnell J, Zeppenfeld D, McConnell E, Pena S, Nedergaard M |title=Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance |journal=Neurochem Res |volume=37 |issue=11 |pages=2496–512 |date=November 2012 |pmid=22717696 |pmc=3548657 |doi=10.1007/s11064-012-0818-x |url=}} After synthesis, norepinephrine is transported from the cytosol into synaptic vesicles by the vesicular monoamine transporter (VMAT).{{cite journal | vauthors = Eiden LE, Schäfer MK, Weihe E, Schütz B | title = The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine | journal = Pflügers Archiv: European Journal of Physiology | volume = 447 | issue = 5 | pages = 636–640 | year=2004 | pmid = 12827358 | doi = 10.1007/s00424-003-1100-5 | s2cid = 20764857 }} 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.

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).{{cite journal | vauthors=Torres GE, Gainetdinov RR, Caron MG | title=Plasma membrane monoamine transporters: structure, regulation and function | journal=Nature Reviews Neuroscience | volume=4 | issue=1 | pages=13–25 | year=2003 | pmid =12511858 | doi=10.1038/nrn1008 | s2cid=21545649 }} 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.

{{main|Sympathetic nervous system}}

File:Blausen 0838 Sympathetic Innervation.png

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.{{cite book |title=Primer on the Autonomic Nervous System |chapter=Peripheral Autonomic Nervous System|vauthors=Hamill RW, Shapiro RE, Vizzard MA |veditors=Robertson D, Biaggioni I, etal |publisher=Academic Press |year=2012 |isbn=978-0-12-386525-0 |pages=17–20}} 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 tissues.

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.{{cite book|title=Psychology: European Edition |vauthors=Schacter D, Gilbert D, Wegner D, Hood B |publisher=Palgrave Macmillan |year=2011 |isbn=978-0-230-34367-2 |page=93}} 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 the production of tears, making the eyes more moist,{{cite journal | vauthors = Dartt DA | title = Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases | journal = Progress in Retinal and Eye Research | volume = 28 | issue = 3 | pages = 155–177 | date = May 2009 | pmid = 19376264 | pmc = 3652637 | doi = 10.1016/j.preteyeres.2009.04.003 }} and pupil dilation through contraction of the iris dilator.
• In the heart, an increase in the amount of blood pumped.{{Cite journal | vauthors = Tank AW, Lee Wong D | title= Peripheral and central effects of circulating catecholamines | journal = Comprehensive Physiology | volume = 5 | issue = 1 | pages = 1–15 | date = January 2015 | pmid = 25589262 | doi = 10.1002/cphy.c140007 | isbn = 978-0-470-65071-4 }}
• In brown adipose tissue, an increase in calories burned to generate body heat (thermogenesis).{{cite journal | vauthors = Bahler L, Molenaars RJ, Verberne HJ, Holleman F | title = Role of the autonomic nervous system in activation of human brown adipose tissue: A review of the literature | journal = Diabetes & Metabolism | volume = 41| issue = 6| date = September 2015 | pmid = 26404650 | doi = 10.1016/j.diabet.2015.08.005 | pages=437–445}}
• 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.{{Cite journal | vauthors = Kenney MJ, Ganta CK |title=Autonomic nervous system and immune system interactions | journal = Comprehensive Physiology | volume = 4 | issue = 3 | pages = 1177–1200 | date = July 2014 | pmid = 24944034 | pmc = 4374437 | doi = 10.1002/cphy.c130051 | isbn = 978-0-470-65071-4 }}
• In the arteries, constriction of blood vessels causes an increase in blood pressure.{{cite journal |vauthors=Chistiakov DA, Ashwell KW, Orekhov AN, Bobryshev YV |title=Innervation of the arterial wall and its modification in atherosclerosis |journal=Autonomic Neuroscience |volume= 193|pages= 7–11|year=2015 |pmid=26164815 |doi=10.1016/j.autneu.2015.06.005 |s2cid=8150131 }}
• In the kidneys, release of renin and retention of sodium in the bloodstream.{{cite journal |vauthors=Thorp AA, Schlaich MP |title=Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome |journal=Journal of Diabetes Research |volume=2015 |pages=1–11 |year=2015 |pmid=26064978 |pmc=4430650 |doi=10.1155/2015/341583 |doi-access=free }}
• 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.{{cite journal |vauthors=Konturek SJ, Konturek JW, Pawlik T, Brzozowski T |title=Brain–gut axis and its role in the control of food intake |journal=Journal of Physiology and Pharmacology |volume=55 |issue=1 Pt 2 |pages=137–154 |year=2004 |pmid=15082874 |url=http://www.jpp.krakow.pl/journal/archive/03_04/pdf/137_03_04_article.pdf}}

Noradrenaline and ATP are sympathetic co-transmitters. It is found that the endocannabinoid anandamide and the cannabinoid WIN 55,212-2 can modify the overall response to sympathetic nerve stimulation, which indicates that prejunctional CB1 receptors mediate the sympatho-inhibitory action. Thus cannabinoids can inhibit both the noradrenergic and purinergic components of sympathetic neurotransmission.{{cite journal | vauthors = Pakdeechote P, Dunn WR, Ralevic V | title = Cannabinoids inhibit noradrenergic and purinergic sympathetic cotransmission in the rat isolated mesenteric arterial bed | journal = British Journal of Pharmacology | volume = 152 | issue = 5 | pages = 725–733 | date = November 2007 | pmid = 17641668 | pmc = 2190027 | doi = 10.1038/sj.bjp.0707397 }}

File:Noradrenergic neurons.png

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").{{cite journal | vauthors = Dahlstroem A, Fuxe K | title = Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons | journal = Acta Physiologica Scandinavica Supplementum | volume = 232 | issue = Supplement 232 | pages = 1–55 | year = 1964 | pmid = 14229500 }} 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.{{cite journal | vauthors = Antunes-Rodrigues J, de Castro M, Elias LL, Valença MM, McCann SM | title = Neuroendocrine control of body fluid metabolism | journal = Physiological Reviews | volume = 84 | issue = 1 | pages = 169–208 | date = January 2004 | pmid = 14715914 | doi = 10.1152/physrev.00017.2003 | s2cid = 14046 | url = http://pdfs.semanticscholar.org/ee3f/0bace9491d84488b0d3c443ceeb627477b19.pdf | archive-url = https://web.archive.org/web/20190306223044/http://pdfs.semanticscholar.org/ee3f/0bace9491d84488b0d3c443ceeb627477b19.pdf | url-status = dead | archive-date = 2019-03-06 }} 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.{{cite journal | vauthors = Rinaman L | title = Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 300 | issue = 2 | pages = R222–R235 | date = February 2011 | pmid = 20962208 | pmc = 3043801 | doi = 10.1152/ajpregu.00556.2010 }} Cell groups A5 and A7 project mainly to the spinal cord.{{cite journal | vauthors = Bruinstroop E, Cano G, Vanderhorst VG, Cavalcante JC, Wirth J, Sena-Esteves M, Saper CB | title = Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats | journal = The Journal of Comparative Neurology | volume = 520 | issue = 9 | pages = 1985–2001 | date = June 2012 | pmid = 22173709 | pmc = 3508755 | doi = 10.1002/cne.23024 }}

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.{{cite journal |vauthors=Sara SJ, Bouret S |title=Orienting and reorienting: the locus coeruleus mediates cognition through arousal |journal=Neuron |volume=76 |issue=1 |pages=130–141 |year=2012 |pmid=23040811 |doi=10.1016/j.neuron.2012.09.011 |doi-access=free }}

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.{{cite journal |vauthors=Berridge CW, Schmeichel BE, España RA |title=Noradrenergic modulation of wakefulness/arousal |journal=Sleep Medicine Reviews |volume=16 |issue=2 |pages=187–197 |year=2012 |pmid=22296742 |pmc=3278579 |doi=10.1016/j.smrv.2011.12.003 }} 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 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.{{cite journal |vauthors=Sara SJ |title=Locus Coeruleus in time with the making of memories |journal=Current Opinion in Neurobiology |volume=35 |pages=87–94 |year=2015 |pmid=26241632 |doi=10.1016/j.conb.2015.07.004 |s2cid=206952441 }} The control of arousal level is strong enough that drug-induced suppression of the LC has a powerful sedating effect.

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 the nucleus gigantocellularis.

Norepinephrine is also produced by Merkel cells which are part of the somatosensory system. It activates the afferent sensory neuron.{{cite journal | vauthors = Feng J, Hu H | title = A novel player in the field: Merkel disc in touch, itch and pain | journal = Experimental Dermatology | volume = 28 | issue = 12 | pages = 1412–1415 | date = December 2019 | pmid = 31001848 | doi = 10.1111/exd.13945 | pmc = 6800577 | doi-access = free }}

{{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.{{cite book |title=Rau's Respiratory Care Pharmacology | vauthors = Gardenhire DS |publisher=Elsevier Health Sciences |year=2013 |isbn=978-0-323-27714-3 |page=88}} 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 pressure. 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.{{cite journal | vauthors = Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP | title = Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 | journal = Critical Care Medicine | volume = 45 | issue = 3 | pages = 486–552 | date = March 2017 | pmid = 28098591 | doi = 10.1097/CCM.0000000000002255 | s2cid = 52827184 | url = http://openaccess.sgul.ac.uk/109148/1/Singer_Surviving%2520Sepsis%2520Campaign%2520Guidelines_CCM.pdf | archive-url = https://web.archive.org/web/20210301040702/http://openaccess.sgul.ac.uk/109148/1/Singer_Surviving%2520Sepsis%2520Campaign%2520Guidelines_CCM.pdf | url-status = dead | archive-date = 1 March 2021 | quote = We recommend norepinephrine as the first-choice vasopressor (strong recommendation, moderate quality of evidence). }}

{{main|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.{{cite journal |vauthors=Deedwania PC |title=Management of Patients With Stable Angina and Type 2 Diabetes |journal=Reviews in Cardiovascular Medicine |volume=16 |issue=2 |pages=105–113 |year=2015 |doi=10.3909/ricm0742 |pmid=26198557 |s2cid=22137234 |doi-access=free }}{{cite journal |vauthors=Mareev Y, Cleland JG |title=Should β-Blockers Be Used in Patients With Heart Failure and Atrial Fibrillation? |journal=Clinical Therapeutics |volume= 37|issue= 10|pages= 2215–2224|year=2015 |pmid=26391145 |doi=10.1016/j.clinthera.2015.08.017 |s2cid=3393256 }} Beta blockers may be a viable choice for other cardiovascular conditions, though, including angina and Marfan syndrome.{{cite journal |vauthors=Kumar A, Agarwal S |title=Marfan syndrome: An eyesight of syndrome |journal=Meta Gene |volume=2 |pages=96–105 |year=2014 |pmid=25606393 |pmc=4287801 |doi=10.1016/j.mgene.2013.10.008 }} They are also widely used to treat glaucoma, most commonly in the form of eyedrops.{{cite journal |vauthors=Inoue K |title=Managing adverse effects of glaucoma medications |journal=Clinical Ophthalmology |volume=8 |pages=903–913 |year=2014 |pmid=24872675 |pmc=4025938 |doi=10.2147/OPTH.S44708 |doi-access=free }} 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.{{cite journal |vauthors=Brugués AO |title=Music performance anxiety. Part 2. A review of treatment options |journal=Medical Problems of Performing Artists |volume=26 |issue=3 |pages=164–171 |year=2011 |pmid=21987072 |doi= 10.21091/mppa.2011.3026}}{{cite journal |vauthors=Fitch K |title=Proscribed drugs at the Olympic Games: permitted use and misuse (doping) by athletes |journal=Clinical Medicine |volume=12 |issue=3 |pages=257–260 |year=2012 |pmid=22783779 |pmc=4953490 |doi= 10.7861/clinmedicine.12-3-257}}

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 with diabetes.

{{main|Alpha blocker}}

These are sympatholytic drugs that block the effects of adrenergic alpha receptors while having little or no effect on beta receptors.{{cite book |title=Pharmacology and the Nursing Process |edition=7th |vauthors=Lilley LL, Collins SR, Snyder JS |publisher=Elsevier Health Sciences |year=2014| isbn=978-0-323-29361-7 |pages=313–316}} 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. Since one of their effects is to inhibit the contraction of the smooth muscle in the prostate, they are often used to treat symptoms of benign prostatic hyperplasia.{{cite journal | vauthors = Hollingsworth JM, Wilt TJ | title = Lower urinary tract symptoms in men | journal = BMJ | volume = 349 | pages = g4474 | date = August 2014 | pmid = 25125424 | pmc = 4688452 | doi = 10.1136/bmj.g4474 }} Alpha-blockers also likely help people pass their kidney stones.{{cite journal | vauthors = Campschroer T, Zhu X, Vernooij RW, Lock MT | title = Alpha-blockers as medical expulsive therapy for ureteral stones | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | pages = CD008509 | date = April 2018 | issue = 4 | pmid = 29620795 | pmc = 6494465 | doi = 10.1002/14651858.CD008509.pub3 }} Their effects on the central nervous system make them useful for treating generalized anxiety disorder, panic disorder, and posttraumatic stress disorder.{{cite journal | vauthors = Green B | title = Prazosin in the treatment of PTSD | journal = Journal of Psychiatric Practice | volume = 20 | issue = 4 | pages = 253–259 | date = July 2014 | pmid = 25036580 | doi = 10.1097/01.pra.0000452561.98286.1e | s2cid = 40069887 }} They may, however, have significant side effects, including a drop in blood pressure.

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.{{cite journal |vauthors=Corazza O, Martinotti G, Santacroce R, Chillemi E, Di Giannantonio M, Schifano F, Cellek S |title=Sexual enhancement products for sale online: raising awareness of the psychoactive effects of yohimbine, maca, horny goat weed, and Ginkgo biloba |journal=BioMed Research International |volume=2014 |pages=1–13 |year=2014 |pmid=25025070 |pmc=4082836 |doi=10.1155/2014/841798 |doi-access=free }} 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. Yohimbine is 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.{{cite journal |journal=EFSA Journal |year=2013 |volume=11 |issue=7 |page=3302 |title=Scientific Opinion on the evaluation of the safety in use of Yohimbe |author=EFSA Panel on Food Additives and Nutrient Sources Added to Food|doi=10.2903/j.efsa.2013.3302|doi-access=free }}

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.{{cite journal |vauthors=Lemke KA |title=Perioperative use of selective alpha-2 agonists and antagonists in small animals |journal=The Canadian Veterinary Journal |volume=45 |issue=6 |pages=475–480 |year=2004 |pmid=15283516 |pmc=548630}} 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 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.{{cite journal |vauthors=Belkin MR, Schwartz TL |title=Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder |journal=Drugs in Context |volume=4 |pages=1–5 |year=2015 |pmid=26322115 |pmc=4544272 |doi=10.7573/dic.212286 }} 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.{{cite journal |vauthors=Greene SA, Thurmon JC |title=Xylazine—a review of its pharmacology and use in veterinary medicine |journal=Journal of Veterinary Pharmacology and Therapeutics |volume=11 |issue=4 |pages=295–313 |year=1988 |pmid=3062194 |doi=10.1111/j.1365-2885.1988.tb00189.x}}

{{See also|Stimulant#Mechanisms of action|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.{{cite journal | vauthors = Sofuoglu M, Sewell RA | title = Norepinephrine and stimulant addiction | journal = Addiction Biology | volume = 14 | issue = 2 | pages = 119–129 | date = April 2009 | pmid = 18811678 | pmc = 2657197 | doi = 10.1111/j.1369-1600.2008.00138.x }} Amphetamine, for example, is a stimulant that increases release of norepinephrine as well as dopamine.{{cite journal | vauthors = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present—a pharmacological and clinical perspective | journal = Journal of Psychopharmacology | volume = 27 | issue = 6 | pages = 479–496 | date = June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 }} Monoamine oxidase A inhibitors (MAO-A) are antidepressants that inhibit the metabolic degradation of norepinephrine as well as serotonin and dopamine.{{cite journal | vauthors = Finberg JP, Rabey JM | title = Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology | language = en | journal = Frontiers in Pharmacology | volume = 7 | pages = 340 | date = 2016 | pmid = 27803666 | doi = 10.3389/fphar.2016.00340 | pmc = 5067815 | quote = Selective inhibition of MAO-A leads to increased levels of neurotransmitter within noradrenergic (NA-ergic) and 5-HT-ergic neurons of the CNS, and clinical antidepressant action, while inhibition of MAO-B leads to increased levels of DA in the Parkinsonian brain... | doi-access = free }} In some cases it is difficult to distinguish the norepinephrine-mediated effects from the effects related to other neurotransmitters.{{citation needed|date=June 2017}}

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,{{cite journal |vauthors=Lump D, Moyer M |title=Paroxysmal sympathetic hyperactivity after severe brain injury |journal=Current Neurology and Neuroscience Reports |volume=14 |issue=11 |pages=494 |year=2014 |pmid=25220846 |doi=10.1007/s11910-014-0494-0 |s2cid=10849388 |doi-access=free }} spinal cord damage,{{cite journal |vauthors=Amzallag M |title=Autonomic hyperreflexia |journal=International Anesthesiology Clinics |volume=31 |issue=1 |pages=87–102 |year=1993 |pmid=8440534 |doi= 10.1097/00004311-199331010-00009|s2cid=32173637 }} heart failure,{{cite journal |vauthors=McCrink KA, Brill A, Lymperopoulos A |title=Adrenal G protein-coupled receptor kinase-2 in regulation of sympathetic nervous system activity in heart failure |journal=World Journal of Cardiology |volume=7 |issue=9 |pages=539–543 |year=2015 |pmid=26413230 |doi=10.4330/wjc.v7.i9.539 |pmc=4577680 |doi-access=free }} high blood pressure,{{cite journal |vauthors=Malpas SC |title=Sympathetic nervous system overactivity and its role in the development of cardiovascular disease |journal=Physiological Reviews |volume=90 |issue=2 |pages=513–557 |year=2010 |pmid=20393193 |doi=10.1152/physrev.00007.2009 }} kidney disease,{{cite journal |vauthors=Ksiazek A, Załuska W |title=Sympathetic overactivity in uremia |journal=Journal of Renal Nutrition |volume=18 |issue=1 |pages=118–121 |year=2008 |pmid=18089457 |doi=10.1053/j.jrn.2007.10.024 }} 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.{{cite journal |vauthors=Chrousos GP |title=Stress and disorders of the stress system |journal=Nature Reviews Endocrinology |volume=5 |issue=7 |pages=374–381 |year=2009 |pmid=19488073 |doi=10.1038/nrendo.2009.106 |s2cid=2259451 |url=https://www.researchgate.net/publication/26258826}} 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 addiction.

Attention deficit hyperactivity disorder is a neurodevelopmental condition involving problems with attention, hyperactivity, and impulsiveness.{{cite journal |vauthors= Kooij SJ, Bejerot S, Blackwell A, Caci H, Casas-Brugué M, Carpentier PJ, Edvinsson D, Fayyad J, Foeken K, Fitzgerald M, Gaillac V, Ginsberg Y, Henry C, Krause J, Lensing MB, Manor I, Niederhofer H, Nunes-Filipe C, Ohlmeier MD, Oswald P, Pallanti S, Pehlivanidis A, Ramos-Quiroga JA, Rastam M, Ryffel-Rawak D, Stes S, Asherson P | title = European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD | journal = BMC Psychiatry | volume = 10 | pages = 67 | year = 2010 | pmid = 20815868 | pmc = 2942810 | doi = 10.1186/1471-244X-10-67 | doi-access = free }} 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.{{cite journal |vauthors=Faraone SV, Bonvicini C, Scassellati C |title=Biomarkers in the diagnosis of ADHD—promising directions |journal=Current Psychiatry Reports |volume=16 |issue=11 |pages=497 |year=2014 |pmid=25298126 |doi=10.1007/s11920-014-0497-1 |s2cid=36702503 }} 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.{{cite journal |vauthors=Bello NT |title=Clinical utility of guanfacine extended release in the treatment of ADHD in children and adolescents |journal=Patient Preference and Adherence |volume=9 |pages=877–885 |year=2015 |pmid=26170637 |pmc=4494608 |doi=10.2147/PPA.S73167 |doi-access=free }}{{cite journal |vauthors=Clemow DB, Bushe CJ |title=Atomoxetine in patients with ADHD: A clinical and pharmacological review of the onset, trajectory, duration of response and implications for patients |journal=Journal of Psychopharmacology |volume= 29|issue= 12|pages= 1221–1230|year=2015 |pmid=26349559 |doi=10.1177/0269881115602489 |s2cid=22649093 }}

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.{{cite journal |vauthors=Shibao C, Okamoto L, Biaggioni I |title=Pharmacotherapy of autonomic failure |journal=Pharmacology & Therapeutics |volume=134 |issue=3 |pages=279–286 |year=2012 |pmid=21664375 |pmc=3358114 |doi=10.1016/j.pharmthera.2011.05.009 }}

Norepinephrine prevents REM sleep, and lack of REM sleep increases noradrenaline secretion{{cite journal | vauthors = Mehta R, Giri S, Mallick BN | title = REM sleep loss-induced elevated noradrenaline could predispose an individual to psychosomatic disorders: a review focused on proposal for prediction, prevention, and personalized treatment | journal = The EPMA Journal | volume = 11 | issue = 4 | pages = 529–549 | date = December 2020 | pmid = 33240449 | pmc = 7680499 | doi = 10.1007/s13167-020-00222-1 }} as a result of the locus coeruleus not ceasing producing it. It causes neurodegeneration if its loss is sustained for several days.{{cite journal | vauthors = Somarajan BI, Khanday MA, Mallick BN | title = Rapid Eye Movement Sleep Deprivation Induces Neuronal Apoptosis by Noradrenaline Acting on Alpha1 Adrenoceptor and by Triggering Mitochondrial Intrinsic Pathway | journal = Frontiers in Neurology | volume = 7 | pages = 25 | date = 2016 | pmid = 27014180 | pmc = 4779900 | doi = 10.3389/fneur.2016.00025 | doi-access = free }}

File:Octopamin.svg, 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),{{cite journal |vauthors=Kass-Simon G, Pierobon P |title=Cnidarian chemical neurotransmission, an updated overview |journal= Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology|volume=146 |issue=1 |pages=9–25 |year=2007 |pmid=17101286 |doi=10.1016/j.cbpa.2006.09.008 }} but not in ctenophores (comb jellies), whose nervous systems differ greatly from those of other animals.{{cite journal |vauthors=Moroz LL |title=Convergent evolution of neural systems in ctenophores |journal=Journal of Experimental Biology |volume=218 |issue=Pt 4 |pages=598–611 |year=2015 |pmid=25696823 |doi=10.1242/jeb.110692 |pmc=4334147|bibcode=2015JExpB.218..598M }} 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.{{cite journal |vauthors=Pflüger HJ, Stevensonb PA |year=2005 |title=Evolutionary aspects of octopaminergic systems with emphasis on arthropods |journal=Arthropod Structure & Development |volume=34 |issue=3 |pages=379–396 |url=https://www.researchgate.net/publication/235927256 |doi=10.1016/j.asd.2005.04.004|bibcode=2005ArtSD..34..379P }} In insects, octopamine has alerting and activating functions that correspond (at least roughly) with the functions of norepinephrine in vertebrates.{{cite journal |vauthors=Verlinden H, Vleugels R, Marchal E, Badisco L, Pflüger HJ, Blenau W, Broeck JV |title=The role of octopamine in locusts and other arthropods |journal=Journal of Insect Physiology |volume=56 |issue=8 |pages=854–867 |year=2010 |pmid=20621695 |doi=10.1016/j.jinsphys.2010.05.018 |bibcode=2010JInsP..56..854V }} 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|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 U.S. pharmacologists between 1934 and 1938 suggested that noradrenaline might be a sympathetic transmitter.{{cite book | vauthors = Bacq ZM |chapter=Chemical transmission of nerve impulses |veditors=Parnham MJ, Bruinvels J |title=Discoveries in Pharmacology, Volume 1 |location=Amsterdam |publisher=Elsevier |year=1983 |pages=49–103 |isbn=978-0-444-80493-8}} In 1939, Hermann Blaschko and Peter Holtz independently identified the biosynthetic mechanism for norepinephrine in the vertebrate body.{{cite journal | vauthors = Blaschko H |year = 1987|title = A half-century of research on catecholamine biosynthesis|journal=Journal of Applied Cardiology|pages = 171–183}}{{cite journal | vauthors = Holtz P |year = 1939 |title =Dopadecarboxylase |language=de |journal = Die Naturwissenschaften|volume = 27|issue = 43 |pages = 724–725 |doi=10.1007/bf01494245|bibcode =1939NW.....27..724H|s2cid = 260483975 }} In 1945 Ulf von Euler published the first of a series of papers that established the role of norepinephrine as a neurotransmitter.{{cite journal | vauthors = von Euler US |year = 1945|title = A sympathomimetic pressor substance in animal organ extracts|journal = Nature|volume = 156|issue = 3949|pages = 18–19| doi =10.1038/156018b0|bibcode =1945Natur.156...18V|s2cid = 4100718}} 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.

{{Reflist|32em}}

• {{Commonscatinline|Norepinephrine}}

{{Neurotransmitters}}

{{Hormones}}

{{Adrenergic receptor modulators}}

{{TAAR ligands}}

{{Phenethylamines}}

{{Authority control}}

Category:TAAR1 agonists

Category:Amphetamine

Category:Alpha-adrenergic agonists

Category:Beta-adrenergic agonists

Category:Neurotransmitters

Category:Hormones

Category:Biology of attention deficit hyperactivity disorder

Category:Catecholamines

Category:Peripherally selective drugs

Category:Phenylethanolamines

Category:Stress hormones