Norepinephrine

Norepinephrine (abbreviated to NE) is also known as noradrenaline or noradrenalin (NA) and it serves both as a hormone and a neurotransmitter in the human body and the brain respectively. This organic chemical compound occurs naturally in our body. Norepinephrine belongs to the catecholamine family. Noradrenaline derives its name from the Latin term that denotes "at or alongside the kidneys". People in the United Kingdom generally prefer the term "noradrenaline", while the name “norepinephrine” is more common in the United States. The word "norepinephrine" is derived from a Greek term.

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The central nervous system produces as well as secretes norepinephrine. In addition, the autonomic nervous system, which is also known as the sympathetic nervous system, also synthesizes and secretes this organic chemical compound. In the brain, the closely packed brain cells known as neurons or nuclei produce norepinephrine. These neurons are very small but have potent effects on the areas of the brain.

Of all the constituents of these nuclei, the locus coeruleus is the most important. The locus coeruleus is found in the pons. The sympathetic ganglia use norepinephrine in the form of a neurotransmitter in the sympathetic nervous system. The sympathetic ganglia are located close to the spinal cord or inside the abdomen. In fact, the adrenal glands also directly release norepinephrine into the bloodstream.

Irrespective of where and how norepinephrine is released, this chemical compound works only on the target cells by attaching itself to and triggering the noradrenergic receptors found on the surface of the cells.

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Usually, norepinephrine works to mobilize the body and the brain for action. Our body releases the lowest amount of norepinephrine when we are asleep and it reaches the highest level when an individual is under duress or is facing any danger, for instance in the supposed fight-to-fight response. The level of this chemical compound in our body starts rising when we are awake.

Working as a neurotransmitter in the brain, it enhances alertness and arousal. At the same time, norepinephrine supports vigilance, improves memory formation as well as retrieval and enhances attention. Norepinephrine also augments anxiety and restlessness. In other parts of the body, this organic chemical compound improves the heart rate as well as blood pressure, activates glucose release from the body's energy storage, enhances blood circulation to the skeletal muscle, lowers blood circulation to the gastrointestinal (GI) system and slows down emptying the bladder, while inhibiting gastrointestinal mobility.

There are various drugs that are medically very important that work by adjusting or changing the norepinephrine systems' actions. By itself, norepinephrine is used extensively in the form of an injectable drug to treat perilously low blood pressure. Often beta blockers, which neutralize some consequences of norepinephrine, are used for treating migraine, glaucoma and a variety of cardiovascular conditions.

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On the other hand, alpha blockers, which work to neutralize another series of effects of norepinephrine, are employed for treating many cardiovascular as well as psychiatric problems. Often, the effect of alpha-2 agonists is sedating and they are generally employed during surgery in the form of anesthesia-enhancers. In addition, alpha-2 agonists are also used to treat alcohol and drug dependence.

Several important drugs used in psychiatry have very potent consequences on the norepinephrine system inside the brain. This results in side-effects, which may be beneficial or detrimental.

Diseases and disorders due to dysfunction of norepinephrine system in the body or brain

When the sympathetic nervous system is hyperactive it itself is not a recognized condition, but it certainly forms a constituent of several different conditions and also possibly a result of consuming sympathomimetic drugs. This leads to a characteristic group of symptoms that may include pains and aches, high blood pressure, fast heartbeat, palpitation, sweating, headache, anxiety, a decline in the glucose level in the bloodstream and even paleness. If the activity of the sympathetic nervous system remains hyperactive for an extended period of time, it may even result in weight loss and various other changes in the body that are related to stress.

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A tumour of the adrenal medulla, pheochromocytoma occurs rarely. This tumour is caused either by specific types of cancer or due to genetic factors. When this tumour occurs, it results in excessive production and secretion of epinephrine and norepinephrine into the bloodstream. Symptoms of this tumour that are most noticeable include sympathetic hyper activation. When this happens, the blood pressure can rise to fatal levels. Removal of the tumour through surgery is the best and most effective means to get rid of the condition.

When we say that an individual is enduring stress, it actually means that he/she is experiencing a situation that actually threatens the body's stability as well as it functioning continuously. In fact, stress can affect a wide assortment of body systems. Among these, the two most constantly activated include the norepinephrine system and the hypothalamic-pituitary-adrenal axis. When the norepinephrine system is activated it includes the sympathetic nervous system as well as the locus coeruleus-centered system which is located inside the brain.

Several types of stressors result in enhanced noradrenergic activity, which, in turn, gather together the brain and the body to deal with the threat. On the other hand, if chronic stress continues for a prolonged period of time, it can damage several body parts. A considerable part of such damages is owing to the continuous release of norepinephrine and its effects on the mind and the body. As a result of massive release of norepinephrine, the resources for its usual function, which includes maintenance, regeneration as well as reproduction, is redirected towards the systems that require it for maintaining their active mobility.

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The results of this are many and may include inhibited growth in children, gastrointestinal problems, sleeplessness, impaired resistance to diseases, loss of libido (sexual urge), depression, sluggish healing of injuries and an enhance vulnerability to any type of addiction.

A psychiatric condition called attention deficit hyperactivity disorder (also referred to as ADHD) is related to problems associated with attention, impulsiveness and hyperactivity.

Most commonly attention deficit hyperactivity disorder is treated with stimulant drugs like methylphenidate (Ritalin), which mainly works to enhance the levels of dopamine in the brain. However, generally medicines in this group also work to enhance norepinephrine levels in the brain. Moreover, it is difficult to ascertain whether or not such actions of these drugs also entail their respective chemical value.

In addition, there is ample substantiation of the fact that several people suffering from ADHD manifest "biomarkers" entailing altered processing of norepinephrine. Several drugs that mainly have an influence on norepinephrine, such as atomoxetine, clonidine and guanfacine, have been tested for treating ADHD and it has been found that their outcome has been somewhat similar to those of the stimulant drugs.

Many health issues, including diabetes, Parkinson's disease and even the supposed genuine autonomic failure, may possibly result in the loss of neurons that secrete norepinephrine in the sympathetic nervous system. The symptoms of such neuron loss are extensive. Among them, the most serious symptoms are decrease in the heart rates and a sharp decline in the resting blood pressure. As a result, people who are severely affected by this condition are virtually unable to stand for few seconds. If they try to stand for some time they are bound to faint.

How norepinephrine works?

Stimulatory as well as inhibitory substances such as presynaptic β-adrenergic and α-adrenergic receptors control the norepinephrine release from the synaptic vesicles. After norepinephrine is released, it attaches itself to the adrenergic receptors found on the surface of the target cells.

Signal transduction mediated by norepinephrine as well as the ultimate functioning of the cells is subject to the variety of receptor (α-adrenergic or β-adrenergic) it binds to. After the work is executed, cellular uptake and subsequent degradation of norepinephrine terminates the signal.

In fact, norepinephrine or noradrenalin is carried back to the presynaptic neuron's cytosol (known as uptake 1). Alternately, it is transported to a close by non-neuronal cell (known as uptake 2). In addition, norepinephrine is transferred from the cytosol to the synaptic vesicle (a process known as vesicular uptake).

Once the uptake is complete, norepinephrine quickly degrades into a variety of metabolies, which include normetanephrine, vanimandelate, dihydroxymandelic acid and epinephrine. Generally, the majority of these metabolites are send out of the body through urine.

Functions of norepinephrine

After norepinephrine is released into the bloodstream from the adrenal medulla, it works as a hormone. On the other hand, when the noradrenergic neurons in the central nervous system and the sympathetic nervous system release norepinephrine, it works as a neurotransmitter.

When norepinephrine is used in the form of a medication, it helps to enhance the vascular tone as well as the blood pressure via α-adrenergic receptors. Owing to this the vascular resistance increases and it starts a negative feedback system, which again works to reduce the heart rate as well as the blood pressure. This entire process is known as baroreceptor reflex.

Norepinephrine also has a vital part in controlling conditional as well as unconditional responses related to fear. When one endures stress, it is occupied in a fight-or-flight mode response to the sympathetic nervous system, which is distinguished by increased heart rate, dilated pupils and elevated blood pressure, profuse sweating, glucose release from the energy stored in the body as well as augmented blood circulation to the skeletal muscles.

In addition to this, norepinephrine plays a crucial role in governing attention and concentration. Majority of the psycho stimulants that are administered for treating attention-deficit hyperactivity disorder (ADHD) actually enhance the levels of dopamine and norepinephrine in the central nervous system.

Compared to β-adrenergic receptors, norepinephrine has a greater affinity for α-adrenergic receptors. As a result of this, it generates a potent vasoconstriction effect. Nevertheless, norepinephrine is not such a potent chronotropic and inotropic agent. Norepinephrine's main hemodynamic function is to augment the systolic, diastolic as well as pulse pressures. It, however, has a very negligible effect on the heart rate and cardiac output. Norepinephrine is used to treat ischemic heart disease, wherein this organic chemical compound is employed to sustain perfusion coronary pressure, but in a way that it does not enhance cardiac output or increase the heart rate. In addition, norepinephrine can also be employed to sustain blood pressure and keep up organ perfusion when there is shock owing to vasodilation, such as in neurogenic shock and septic shock.

The major neurotransmitter mostly employed by the sympathetic nervous system is norepinephrine. The sympathetic nervous system comprises roughly 24 sympathetic chain ganglia that are found adjacent to the spinal cord. In addition, it has a group of prevertebral ganglia that are present in the abdomen and chest. The sympathetic ganglia are linked to various organs in our body, which includes the heart, liver, lungs, kidneys, salivary glands, eyes, adrenal glands, stomach, gallbladder, urinary bladder, intestines, skin, muscles and also the reproductive organs.

When the sympathetic ganglia in the adrenal glands are activated, it leads to a part known as the adrenal medulla to discharge norepinephrine into our bloodstream. Here, norepinephrine functions as a hormone and it gets the right of entry into various tissues.

Generally speaking, norepinephrine acts on every target organ in the body to adapt its condition in such a manner that makes these target organs further conducive to make the body movement more active. Often this is done at the cost of consuming more energy as well as further wear and tear. In fact, these actions are in contrast to the affects mediated by acetylcholine related to the parasympathetic nervous system. Contrary to the action of the sympathetic nervous system, the parasympathetic nervous system modifies the very same target organs into a condition that is further conducive to recovery, rest as well as digesting food. And all these are done by consuming very less energy.

Similar to several other substances that are biologically active, norepinephrine makes use of its effects by attaching to and triggering the receptors that are found outside the cells.

So far scientists have identified two general norepinephrine receptor families, which are known as alpha adrenergic and beta adrenergic receptors. Among the two, the alpha adrenergic receptors are further divided into two subtypes - α1 and α2. On the other hand, the beta adrenergic receptors are divided into three subtypes - β1, β2, and β3. All these different types of receptors work as G protein-coupled receptors. In other words, they put forth their effects through a multifaceted second messenger network.

Usually, the effect of the alpha-2 adrenergic receptors is inhibitory, but several of them are found in the pre-synaptically (meaning that they are found on the exterior of the cells that discharge norepinephrine). Hence, when the alpha-2 adrenergic receptors are activated, often it results in decreased norepinephrine release. On the other hand, generally the effect of the alspha-1 adrenergic receptors and all the three types of beta adrenergic receptors is excitatory.

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