Norepinephrine

Norepinephrine is a catecholamine and a phenethylamine. Its structure differs from that of epinephrine only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. 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. ==Biochemical mechanisms==

Biosynthesis 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. 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. 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. 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. == Functions ==

Cellular effects 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. After synthesis, norepinephrine is transported from the cytosol into synaptic vesicles by the vesicular monoamine transporter (VMAT). 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 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. 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. 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. and pupil dilation through contraction of the iris dilator. • In the heart, an increase in the amount of blood pumped. • In brown adipose tissue, an increase in calories burned to generate body heat (thermogenesis). • Multiple effects on the immune system. The sympathetic nervous system is the primary path of interaction between the immune system and the brain, and several components receive sympathetic inputs, including the thymus, spleen, and lymph nodes. However, the effects are complex, with some immune processes activated while others are inhibited. • In the arteries, constriction of blood vessels causes an increase in blood pressure. • In the kidneys, release of renin and retention of sodium in the bloodstream. • 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. 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. Central nervous system 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"). In their scheme, areas A1 through A7 contain the neurotransmitter norepinephrine (A8 through A14 contain dopamine). Noradrenergic cell group A1 is located in the caudal ventrolateral part of the medulla, and plays a role in the control of body fluid metabolism. Noradrenergic cell group A2 is located in a brainstem area called the solitary nucleus; these cells have been implicated in a variety of responses, including control of food intake and responses to stress. Cell groups A5 and A7 project mainly to the spinal cord. The most important source of norepinephrine in the brain is the locus coeruleus, which contains noradrenergic cell group A6 and adjoins cell group A4. The locus coeruleus is quite small in absolute terms—in primates, it is estimated to contain around 15,000 neurons, less than one-millionth of the neurons in the brain—but it sends projections to every major part of the brain and also to the spinal cord. The level of activity in the locus coeruleus correlates broadly with vigilance and speed of reaction. LC activity is low during sleep and drops to virtually nothing during the REM (dreaming) state. It runs at a baseline level during wakefulness, but increases temporarily when a person is presented with any sort of stimulus that draws attention. Unpleasant stimuli such as pain, difficulty breathing, bladder distension, heat or cold generate larger increases. Extremely unpleasant states such as intense fear or intense pain are associated with very high levels of LC activity. The control of arousal level is strong enough that drug-induced suppression of the LC has a powerful sedating effect. ==Pharmacology==

A large number of important drugs exert their effects by interacting with norepinephrine systems in the brain or body. Their uses include treatment of cardiovascular problems, shock, and a variety of psychiatric conditions. These drugs are divided into: sympathomimetic drugs which mimic or enhance at least some of the effects of norepinephrine released by the sympathetic nervous system; sympatholytic drugs, in contrast, block at least some of the effects. Both of these are large groups with diverse uses, depending on exactly which effects are enhanced or blocked. Antagonists Beta blockers These are sympatholytic drugs that block the effects of beta adrenergic receptors while having little or no effect on alpha receptors. They are sometimes used to treat high blood pressure, atrial fibrillation, and congestive heart failure, but recent reviews have concluded that other types of drugs are usually superior for those purposes. Beta blockers may be a viable choice for other cardiovascular conditions, though, including angina and Marfan syndrome. They are also widely used to treat glaucoma, most commonly in the form of eyedrops. Because of their effects in reducing anxiety symptoms and tremor, they have sometimes been used by entertainers, public speakers, and athletes to reduce performance anxiety, although they are not medically approved for that purpose and are banned by the International Olympic Committee. However, the usefulness of beta blockers is limited by a range of serious side effects, including slowing of heart rate, a drop in blood pressure, asthma, and reactive hypoglycemia. 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-blockers also likely help people pass their kidney stones. Their effects on the central nervous system make them useful for treating generalized anxiety disorder, panic disorder, and posttraumatic stress disorder. They may, however, have significant side effects, including a drop in blood pressure. Yohimbine acts as a male potency enhancer, but its usefulness for that purpose is limited by serious side-effects including anxiety and insomnia. Alpha-2 agonists These are sympathomimetic drugs that activate alpha-2 receptors or enhance their effects. 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. Xylazine, another drug in this group, is also a powerful sedative and is often used in combination with ketamine as a general anaesthetic for veterinary surgery—in the United States it has not been approved for use in humans. Stimulants and antidepressants These are drugs whose primary effects are thought to be mediated by different neurotransmitter systems (dopamine for stimulants, serotonin for antidepressants), but many also increase levels of norepinephrine in the brain. Amphetamine, for example, is a stimulant that increases release of norepinephrine as well as dopamine. Monoamine oxidase A inhibitors (MAO-A) are antidepressants that inhibit the metabolic degradation of norepinephrine as well as serotonin and dopamine. In some cases it is difficult to distinguish the norepinephrine-mediated effects from the effects related to other neurotransmitters. ==Diseases and disorders==

A number of important medical problems involve dysfunction of the norepinephrine system in the brain or body. 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, spinal cord damage, heart failure, high blood pressure, kidney disease, 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 Stress, to a physiologist, means any situation that threatens the continued stability of the body and its functions. Stress affects a wide variety of body systems: the two most consistently activated are the hypothalamic-pituitary-adrenal axis and the norepinephrine system, including both the sympathetic nervous system and the locus coeruleus-centered system in the brain. 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. 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. 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. REM sleep deprivation Norepinephrine prevents REM sleep, and lack of REM sleep increases noradrenaline secretion as a result of the locus coeruleus not ceasing producing it. It causes neurodegeneration if its loss is sustained for several days. ==Comparative biology and evolution==

, 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, but not in ctenophores (comb jellies), whose nervous systems differ greatly from those of other animals. It is generally present in deuterostomes (vertebrates, etc.), but in protostomes (arthropods, molluscs, flatworms, nematodes, annelids, etc.) it is replaced by octopamine, a closely related chemical with a closely related synthesis pathway. In insects, octopamine has alerting and activating functions that correspond (at least roughly) with the functions of norepinephrine in vertebrates. It has been argued that octopamine evolved to replace norepinephrine rather than vice versa; however, the nervous system of amphioxus (a primitive chordate) has been reported to contain octopamine but not norepinephrine, which presents difficulties for that hypothesis. ==History==

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. In 1939, Hermann Blaschko and Peter Holtz independently identified the biosynthetic mechanism for norepinephrine in the vertebrate body. In 1945 Ulf von Euler published the first of a series of papers that established the role of norepinephrine as a neurotransmitter. He demonstrated the presence of norepinephrine in sympathetically innervated tissues and brain, and adduced evidence that it is the sympathin of Cannon and Rosenblueth. Stanley Peart was the first to demonstrate the release of noradrenaline after the stimulation of sympathetic nerves. ==References==