[Met]enkephalin, sometimes referred to as opioid growth factor (OGF), is a naturally-occurring

Natural product

A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...

, endogenous

Endogenous

Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

 opioid peptide

Opioid peptide

Opioid peptides are short sequences of amino acids that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Opioid peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble opiates...

 that has opioid

Opioid

An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

 effects of a relatively short duration. It is one of the two forms of enkephalin

Enkephalin

An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were revealed, one...

, the other being [leu]enkephalin

Leu-enkephalin

Leu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met-enkephalin. The tyrosine residue at position 1 is...

. The enkephalins are considered to be the primary endogenous ligands of the δ-opioid receptor, due to their high potency

Potency (pharmacology)

In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...

 and selectivity

Binding selectivity

Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...

 for the site over the other endogenous opioids.

History

[Met]enkephalin was discovered and characterized by Hughes, Kosterlitz, et al. in 1975 after a diligent and intensive search for endogenous ligands of the opioid receptors.

Chemistry

[Met]enkephalin is a pentapeptide with the amino acid sequence Tyr-Gly-Gly-Phe-Met.

The tyrosine

Tyrosine

Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...

 residue

Residue (chemistry)

In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....

 at position 1 is thought to be analogous to the 3-hydroxyl

Hydroxyl

A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...

 group

Functional group

In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...

 on morphine

Morphine

Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...

.

Distribution

[Met]enkephalin is found mainly in the adrenal medulla

Adrenal medulla

The adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete epinephrine , norepinephrine , and a small amount of dopamine in response to...

 and throughout the central nervous system

Central nervous system

The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 (CNS), including in the striatum

Striatum

The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...

, cerebral cortex

Cerebral cortex

The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...

, olfactory tubercle

Olfactory tubercle

The olfactory tubercle is a structure involved in Olfaction.It is present in humans, but much smaller than it is in some other animals.It is a frequent subject of research.-External links:...

, hippocampus

Hippocampus

The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...

, septum

Septum

In anatomy, a septum is a wall, dividing a cavity or structure into smaller ones.-In human anatomy:...

, thalamus

Thalamus

The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...

, and periaqueductal gray

Periaqueductal gray

Periaqueductal gray is the gray matter located around the cerebral aqueduct within the tegmentum of the midbrain. It plays a role in the descending modulation of pain and in defensive behaviour...

, as well as the dorsal horn of the spinal cord

Spinal cord

The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

. It is also present in the periphery

Periphery

Periphery may refer to:* Peripheries of Greece, the administrative subdivisions of that country* Periphery * Periphery , by Periphery* Periphery * Periphery countries, a category of less-developed nations...

, notably in some primary afferent fiber

Type Ia sensory fiber

Type Ia Sensory Fiber also called Primary Afferent Fiber is a type of sensory fiber. It is a component of a muscle fiber's muscle spindle which keeps track of how fast a muscle stretch changes .-Function of muscle spindles:...

s that innervate the pelvic viscera.

Biosynthesis

[Met]enkephalin is synthesized from proenkephalin A via proteolyic

Protease

A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

 cleavage

Bond cleavage

Bond cleavage, or scission, is the splitting of chemical bonds.If the two electrons in a cleaved covalent bond are divided between the products, the process is known as homolytic fission and free redicals are generated by homolytic cleavage the process is known as homolytic fission or homolysis...

 in two metabolic

Metabolism

Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

 steps. Proenkephalin A is first reduced by either one of two trypsin

Trypsin

Trypsin is a serine protease found in the digestive system of many vertebrates, where it hydrolyses proteins. Trypsin is produced in the pancreas as the inactive proenzyme trypsinogen. Trypsin cleaves peptide chains mainly at the carboxyl side of the amino acids lysine or arginine, except when...

-like endopeptidase

Endopeptidase

Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids , in contrast to exopeptidases, which break peptide bonds from their end-pieces. For this reason, endopeptidases cannot break down peptides into monomers, while exopeptidases can break...

 enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s, prohormone convertase 1 (PC1) or prohormone convertase 2 (PC2); then, the resulting intermediate

Reaction intermediate

A reaction intermediate or an intermediate is a molecular entity that is formed from the reactants and reacts further to give the directly observed products of a chemical reaction. Most chemical reactions are stepwise, that is they take more than one elementary step to complete...

s are further reduced by the enzyme carboxypeptidase E

Carboxypeptidase E

Carboxypeptidase E, also known as carboxypeptidase H and enkephalin convertase, is an enzyme that in humans is encoded by the CPE gene....

 (CPE; previously known as enkephalin convertase (EC)). Proenkephalin A contains four sequences of [Met]enkephalin (at the following positions: 100-104; 107-111; 136-140; 210-214), and as a result, its cleavage generates four copies of [Met]enkephalin peptides at once. In addition, anabolism of proenkephalin A results in the production of one copy each of two C-terminal-extended [Met]enkephalin derivatives

Derivative (chemistry)

In chemistry, a derivative is a compound that is derived from a similar compound by some chemical or physical process. In the past it was also used to mean a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms, but modern...

, the heptapeptide [Met]enkephalin-Arg-Phe (261-267), and the octapeptide [Met]enkephalin-Arg-Gly-Leu (186-193), though whether they affect the opioid receptors in a similar manner as [Met]enkephalin is not entirely clear.

Clearance

[Met]- and [Leu]enkephalin are metabolized by a variety of different enzymes, including aminopeptidase N (APN), neutral endopeptidase (NEP), dipeptidyl peptidase 3 (DPP3), carboxypeptidase A6

Carboxypeptidase A6

Carboxypeptidase A6 is an metallocarboxypeptidase enzyme that in humans is encoded by the CPA6 gene. It is highly expressed in the adult mouse olfactory bulb and is broadly expressed in the embryonic brain and other tissues....

 (CPA6), and angiotensin-converting enzyme

Angiotensin-converting enzyme

Angiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...

 (ACE). Collectively, these enzymes are known as the enkephalinase

Enkephalinase

Enkephalinases are enzymes which degrade endogenous enkephalin opioid peptides. They include:* Aminopeptidase N * Neutral endopeptidase * Dipeptidyl peptidase 3 * Carboxypeptidase A6 * Angiotensin-converting enzyme...

s.

Pharmacodynamics

[Met]enkephalin is a potent

Potency (pharmacology)

In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...

 agonist

Agonist

An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

 of the δ-opioid receptor, and to a lesser extent the μ-opioid receptor, with little to no effect on the κ-opioid receptor. It is through these receptors that [Met]enkephalin produces its opioid effects, such as analgesia and mood lift

Antidepressant

An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

.

It is also the endogenous ligand

Ligand (biochemistry)

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...

 of the opioid growth factor receptor (OGFR; formerly known as the ζ-opioid receptor), which plays a role in the regulation of tissue growth and regeneration; hence why [Met]enkephalin is sometimes called OGF instead.

Pharmacokinetics

[Met]enkephalin has low bioavailability

Bioavailability

In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

, is rapidly metabolized, and has a very short half-life

Half-life

Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

(minutes).