NOREPINEPHRINE: STRUCTURE, FUNCTIONS, MECHANISM OF ACTION - NEUROPSYCHOLOGY - 2025

The norepinephrine, also called noradrenaline, is a chemical organic that belongs to the family of catecholamines. It acts within the body and the brain, alternating between functions as a neurotransmitter or as a hormone depending on the case. The name comes from a Greek term that means "in the kidneys", due to the area in which it is synthesized.

The main function of norepinephrine is to activate both the body and the brain, with the intention of preparing them for action. It is at its lowest point during sleep, and its levels rise during wakefulness; But it is not until a stressful situation occurs that it reaches its highest point, in what are known as fight or flight responses.

Norepinephrine. By: AndreaAP96

When active, it causes increased attention, improves memory-related functions, and increases alertness. At the body level, it is responsible for increasing blood pressure and circulatory flow to the muscles, as well as increasing the release of glucose from energy stores and reducing irrigation in the gastrointestinal and excretory system.

Research shows that the main function of norepinephrine is to prepare the body and mind to face immediate danger, such as a physical attack by a predator.

However, this substance can also be activated in stressful situations where there is no specific danger, such as when stress levels increase.

Structure

Norepinephrine is part of the group of catecholamines and phenethylamines. Its structure is very similar to that of epinephrine, with the only difference that the latter has a methyl group attached to its nitrogen. On the contrary, in norepinephrine this methyl group is replaced by a hydrogen atom.

The prefix "nor-" is an abbreviation of the word "normal." This is used to indicate that norepinephrine is a demethylated compound.

This substance is produced from tyrosine, an amino acid that undergoes a series of transformations within the adrenal medulla and postganglionic neurons, within the sympathetic nervous system.

The complete sequence is as follows: phenylalanine is converted to tyrosine through the action of the enzyme phenylalanine hydroxylase. Afterwards, tyrosine undergoes a hydroxidation process, which transforms it into L-DOPA. The next step involves the transformation of this substance into dopamine, thanks to the action of the aromatic enzyme DOPA decarboxylase.

Finally, dopamine is eventually transformed into norepinephrine due to the action of the enzyme dopamine β-monooxygenase, which uses oxygen and ascorbic acid as cofactors.

Furthermore, it should be noted that norepinephrine can end up being transformed into epinephrine through the action of phenylethanolamine N-methyltransferase, although this does not occur in all cases.

Functions of norepinephrine

Areas of the brain that contain noradrenergic neurons. Source: Pancrat, wikimedia commons

Norepinephrine, being part of one of the most important hormone and neurotransmitter systems in the body, fulfills a large number of functions. These can be divided into three groups: those that occur within the central nervous system, and those related to the sympathetic nervous system.

Functions in the central nervous system

Noradrenergic neurons in the brain form a neurotransmission system that affects a large number of cortical areas when activated. The main effects can be seen in the form of a state of alertness and activation, which predisposes the person to take action.

Neurons that are primarily activated by norepinephrine do not form a very large percentage within the brain, and are found mostly in a small group of areas in the brain; but its effects are distributed throughout the cerebral cortex.

The level of activation caused by norepinephrine has an immediate effect on the reaction rate, increasing it; and it also improves the ability to be alert. In general, the locus ceruleus (the main brain structure related to norepinephrine) is in a relaxed state during sleep, and activated during wakefulness.

On the other hand, when a person is faced with stressful stimuli such as very cold or heat, breathing difficulties, pain, fear or anxiety, the locus ceruleus is activated to a greater extent.

At this time, the brain processes information from the sense organs more efficiently, and the person's ability to pay attention to their surroundings increases.

In addition to this, norepinephrine at the brain level slows down or even stops conscious thought processes, because it promotes a full alertness that helps you detect any danger or problem in your environment. Also, a side effect of this is the improvement of the processes of creating new memories.

Functions in the sympathetic nervous system

In the same way that norepinephrine causes an alert state in the brain, in the parasympathetic nervous system it creates a series of reactions that promote the activation of the whole body.

In fact, it is the main hormone used by this body subsystem, which is connected to a large number of organs and structures, from muscles to the heart, eyes, lungs, and skin.

In general, the main effect of norepinephrine in the body is to alter the state of a large number of organs in such a way that the movement of the body is enhanced, at the cost of a higher level of physical stress and a very high expenditure of Energy.

Some of the effects of norepinephrine within the sympathetic nervous system are as follows:

- Increase in the amount of blood pumped by the heart.

- Dilation of the pupils and production of a greater quantity of tears, in order to moisten the eyes and allow them to remain open for longer.

- Increased burning of brown fat, in order to achieve a higher level of energy available in the body.

- Increased production of glucose in the liver, to use this substance as immediate fuel.

- Reduction of digestive activity, to concentrate all the resources of the body in movement and in a possible fight or flight response.

- Preparation of the muscles to give a quick and forceful response, mainly by increasing blood circulation to them.

Mechanism of action

Norepinephrine processing at a synapse. Source: Pancrat, wikimedia commons

As with many other hormones and neurotransmitters, norepinephrine produces its effects by binding to specific receptors for it on the surface of certain cells. Specifically, two types of receptors for norepinephrine have been identified: alpha and beta.

Alpha receptors are divided into two subtypes: α ₁ and α ₂. On the other hand, the beta is divided into β ₁, β ₂, and β ₃. Both alpha 1 and all three beta subtypes have excitatory effects in the body; and alpha 2 play an inhibitory role, but most of them are located in presynaptic cells, so they do not play such an important role in the effects of this substance.

Within the brain, norepinephrine behaves like a neurotransmitter, therefore it follows a function that is common to all monoamine neurotransmitters.

After its production, this substance goes to the cytosol attached to the vesicular monoamine transporter (VMAT). The norepinephrine then stays at rest within these vesicles until it is released by an action potential.

Once norepinephrine has been released into the postsynaptic cell, it binds to and activates its receptors, producing the effects we have already mentioned in the brain and in the body.

Afterwards, it is reabsorbed by the body, and can then be transformed into other substances or re-enter a state of rest within the VMAT.

Medical uses

Norepinephrine degradation. The metabolizing enzymes are shown in boxes. Source: Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJour nal of Medicine

The mechanism of action of norepinephrine is used to make a large number of drugs. Many of them serve to mimic the effects that this substance naturally causes in the body; but others can be used as antagonists of the sympathetic nervous system, thus relaxing the organism. Here we will see some of the most important.

Alpha blockers

Alpha blockers are drugs that block the effects of alpha adrenergic receptors, while having little effect on beta receptors. Within this group, we can find some drugs that block alpha 1, alpha 2 receptors, or both. Depending on what your goal is, they can have very different effects.

For example, drugs that block alpha 2 receptors cause an increase in the levels of norepinephrine released in the body, and therefore potentiate the effects of this substance.

On the other hand, drugs that block alpha 1 receptors reduce the amount of norepinephrine molecules that come to bind with postsynaptic cells, reducing the effects of this substance.

Thus, for example, they can be used as muscle relaxants, or as anxiolytics, especially in psychological conditions such as panic disorders or generalized anxiety disorder.

Beta blockers

Beta blockers reduce the number of norepinephrine molecules that can bind to beta receptors on postsynaptic cells. They are used primarily to treat conditions with high levels of blood pressure.

Although in some cases they have positive effects on anxiety, in most countries they are not medically approved for this use.

References

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4. "What's the Difference Between Epinephrine and Norepinephrine?" in: Health Line. Retrieved on: June 19, 2019 from Health Line: healthline.com.
5. "Norepinephrine" in: Wikipedia. Retrieved on: June 19, 2019 from Wikipedia: en.wikipedia.org.