Norepinephrine

Norepinephrine, also called noradrenaline or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "norepinephrine", "upon", and νεφρός is usually preferred in the United States, whereas "noradrenaline" is more commonly used in the United Kingdom and the rest of the world. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.
The general function of norepinephrine is to mobilize the brain and body for action. Norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the rest of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility.
In the brain, noradrenaline is produced in nuclei that are small yet exert powerful effects on other brain areas. The most important of these nuclei is the locus coeruleus, located in the pons. Outside the brain, norepinephrine is used as a neurotransmitter by sympathetic ganglia located near the spinal cord or in the abdomen, as well as 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. Noradrenaline itself is widely used as an injectable drug for the treatment of critically low blood pressure. Stimulants often increase, enhance, or otherwise act as agonists of norepinephrine. Drugs such as cocaine and methylphenidate act as reuptake inhibitors of norepinephrine, as do some antidepressants, such as those in the SNRI class. One of the more notable drugs in the stimulant class is amphetamine, which acts as a dopamine and norepinephrine analog, reuptake inhibitor, as well as an agent that increases the amount of global catecholamine signaling throughout the nervous system by reversing transporters in the synapses. 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 and decreasing the rate of relaxation during diastole, 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 or alcohol dependence. For reasons that are still unclear, some Alpha-2 agonists, such as guanfacine, have also been shown to be effective in the treatment of anxiety disorders and ADHD. Many important psychiatric drugs exert strong effects on noradrenaline systems in the brain, resulting in effects that may be helpful or harmful.

Structure

Norepinephrine is a catecholamine and a phenethylamine. Its structure differs from that of epinephrine only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix nor- is derived as an abbreviation of the word "normal", used to indicate a demethylated compound. Norepinephrine consists of a catechol moiety, 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. The metabolic pathway is:
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 and tetrahydrobiopterin as cofactors. Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O₂, and probably ferrous iron as cofactors. 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, with pyridoxal phosphate as a cofactor. Dopamine is then converted into norepinephrine by the enzyme dopamine β-monooxygenase, 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.

Degradation

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 or COMT. From there, the breakdown can proceed by a variety of pathways. The principal end products are either Vanillylmandelic acid or a conjugated form of MHPG, both of which are thought to be biologically inactive and are excreted in the urine.

Functions

Cellular effects

Family	Receptor	Type	Mechanism
Alpha	α₁	G_q-coupled.	Increase IP₃ and calcium by activating phospholipase C.
Alpha	α₂	G_i/G_o-coupled.	Decrease cAMP by inhibiting adenylate cyclase.
Beta	β₁	G_s-coupled.	Increase cAMP by activating adenylate cyclase.
Beta	β₂	G_s-coupled.	Increase cAMP by activating adenylate cyclase.
Beta	β₃	G_s-coupled.	Increase cAMP by activating adenylate cyclase.

Like many other biologically active substances, norepinephrine exerts its effects by binding to and activating receptors located on the surface of cells. Two broad families of norepinephrine receptors have been identified, known as alpha and beta-adrenergic receptors. Alpha receptors are divided into subtypes α₁ and α₂; beta receptors into subtypes β₁, β₂, and β₃. All of these function as G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system. Alpha-2 receptors usually have inhibitory effects, but many are located pre-synaptically, so the net effect of alpha-2 activation is often a decrease in the amount of norepinephrine released. Alpha-1 receptors and all three types of beta receptors usually have excitatory effects.

Storage, release, and reuptake

Inside the brain norepinephrine functions as a neurotransmitter and neuromodulator, and is controlled by a set of mechanisms common to all monoamine neurotransmitters. After synthesis, norepinephrine is transported from the cytosol into synaptic vesicles by the vesicular monoamine transporter. 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. 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.

Sympathetic nervous system

Norepinephrine is the main neurotransmitter used by the sympathetic nervous system, which consists of about two dozen sympathetic chain ganglia located next to the spinal cord, plus a set of prevertebral ganglia located in the chest and abdomen. These sympathetic ganglia are connected to numerous organs, including the eyes, salivary glands, heart, lungs, liver, gallbladder, stomach, intestines, kidneys, urinary bladder, reproductive organs, muscles, skin, and adrenal glands. Sympathetic activation of the adrenal glands causes the part called the adrenal medulla to release norepinephrine 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. 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, 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.
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. 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, 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.

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.