The μ-opioid receptors (MOR) are a class of opioid receptor

Opioid receptor

Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...

s with high affinity for 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...

s and beta-endorphin

Beta-endorphin

β-endorphin is an endogenous opioid peptide neurotransmitter found in the neurons of both the central and peripheral nervous system.The amino acid sequence is:...

 but low affinity for dynorphin

Dynorphin

Dynorphins are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 , multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin...

s. They are also referred to as μ opioid peptide

Peptide

Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 (MOP) receptors. The prototypical μ receptor 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...

 is the opium

Opium

Opium is the dried latex obtained from the opium poppy . Opium contains up to 12% morphine, an alkaloid, which is frequently processed chemically to produce heroin for the illegal drug trade. The latex also includes codeine and non-narcotic alkaloids such as papaverine, thebaine and noscapine...

 alkaloid

Alkaloid

Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 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...

; μ (mu) refers to morphine.

Types

There are three well-characterized variants of the μ opioid receptor, though reverse-transcriptase PCR has identified up to 10 total splice variants in humans.

More is known about the μ₁ opioid receptor than is known about the other types, but some information does exist. TRIMU 5

TRIMU 5

TRIMU 5 is a selective agonist of the mu-2 mu opioid receptor....

 is a selective agonist of the μ₂ receptor.

In 2003, a μ₃ variant was described, which was responsive to opiate alkaloid

Alkaloid

Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

s but not opioid peptide

Peptide

Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

s.

Location

They can exist either presynaptically or postsynaptically depending upon cell types.

The μ-receptors exist mostly presynaptically in the 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...

 region, and in the superficial 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...

 (specifically the substantia gelatinosa of Rolando

Substantia gelatinosa of Rolando

The apex of the posterior horn of the gray matter of the spinal cord is capped by a V-shaped or crescentic mass of translucent, gelatinous neuroglia, termed the substantia gelatinosa of Rolando , which contains both neuroglia cells, and small nerve cells...

). Other areas where μ-receptors have been located include the external plexiform layer of the olfactory bulb

Olfactory bulb

The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...

, the nucleus accumbens

Nucleus accumbens

The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...

, in several layers of the 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...

 and in some of the nuclei

Nucleus (neuroanatomy)

In neuroanatomy, a nucleus is a brain structure consisting of a relatively compact cluster of neurons. It is one of the two most common forms of nerve cell organization, the other being layered structures such as the cerebral cortex or cerebellar cortex. In anatomical sections, a nucleus shows up...

 of the amygdala

Amygdala

The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...

, as well as the nucleus of the solitary tract.

μ receptors are also found in the intestinal tract. This causes constipation, a major side effect of μ agonists, due to inhibition of peristaltic action.

Activation

MOR can mediate acute changes in neuronal excitability via "disinhibition" of presynaptic release of GABA

Gamma-aminobutyric acid

γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...

 (see works from Charles Chavkin and Roger Nicoll). Activation of the MOR leads to different effects on dendritic spines depending upon the agonist, and may be an example of functional selectivity

Functional Selectivity

Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...

 at the μ receptor. The physiological and pathological roles of these two distinct mechanisms remain to be clarified. Perhaps, both might be involved in opioid addiction and opioid-induced deficits in cognition.

Activation of the μ receptor by an agonist such as 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...

 causes analgesia, sedation

Sedation

Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...

, slightly reduced blood pressure

Blood pressure

Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...

, itching, nausea

Nausea

Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, euphoria

Euphoria

Euphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...

, decreased respiration, miosis

Miosis

Miosis is the constriction of the pupil of the eye to two millimeters or less...

 (constricted pupils) and decreased bowel motility often leading to constipation

Constipation

Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

. Some of these side effects, such as sedation, euphoria and decreased respiration, tend to lessen with continued use as tolerance develops. Analgesia, miosis and reduced bowel motility tend to persist; little tolerance develops to these effects.

The canonical MOR1 isoform is responsible for morphine-induced analgesia whereas the alternatively spliced MOR1D isoform (through heterodimerization with the gastrin-releasing peptide receptor

Gastrin-releasing peptide receptor

The gastrin-releasing peptide receptor , now properly known as BB2 is a G protein-coupled receptor whose endogenous ligand is gastrin releasing peptide...

) is required for morphine-induced itching.

Deactivation

As with other G protein-coupled receptor

G protein-coupled receptor

G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...

s, signalling by the mu opioid receptor is terminated through several different mechanisms, which are upregulated with chronic use, leading to rapid tachyphylaxis

Tachyphylaxis

Tachyphylaxis is a medical term describing a decrease in the response to a drug due to previous exposure to that drug. Increasing the dose of the drug may be able to restore the original response. In this context tachyphylaxis is a synonym for drug tolerance...

. The most important regulatory proteins for the mu opioid receptor are the β-arrestins

Arrestin

Arrestins are a small family of proteins important for regulating signal transduction.-Function:Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors in the visual rhodopsin system by Hermann Kühn and co-workers and...

 Arrestin beta 1

Arrestin beta 1

Arrestin, beta 1, also known as ARRB1, is a protein which in humans is encoded by the ARRB1 gene.- Function :Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G protein-coupled receptors and cause specific dampening of cellular...

 and Arrestin beta 2

Arrestin beta 2

Beta-arrestin-2, also known as arrestin beta-2, is an intracellular protein that in humans is encoded by the ARRB2 gene.Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G protein-coupled receptors and cause specific dampening of...

, and the RGS proteins

Regulator of G protein signalling

Regulators of G protein signalling are protein structural domains that activate GTPases for heterotrimeric G-protein alpha-subunits....

 RGS4

RGS4

Regulator of G protein signaling 4 or RGS4 is a protein which regulates G protein signaling. A number of studies associate the RGS4 gene with schizophrenia, while some fail to detect an association....

, RGS9-2

RGS9

Regulator of G-protein signalling 9, also known as RGS9, is a human gene, which codes for a protein involved in regulation of signal transduction inside cells...

, RGS14

RGS14

Regulator of G-protein signaling 14 is a protein that in humans is encoded by the RGS14 gene.- Function :RGS14 is a member of the regulator of G protein signalling family. This protein contains one RGS domain, two Raf-like Ras-binding domains , and one GoLoco motif...

 and RGSZ2

RGS17

Regulator of G-protein signaling 17 is a protein that in humans is encoded by the RGS17 gene.This gene encodes a member of the regulator of G-protein signaling family. This protein contains a conserved, 120 amino acid motif called the RGS domain and a cysteine-rich region...

.

Long-term or high dose use of opioids may also lead to additional mechanisms of tolerance becoming involved. This includes downregulation of mu opioid receptor gene expression, so the number of receptors presented on the cell surface is actually reduced, as opposed to the more short-term desensitisation induced by β-arrestins or RGS proteins. Another long-term adaptation to opioid use can be upregulation of glutamate and other pathways in the brain which can exert an opioid-opposing effect and so reduce the effects of opioid drugs by altering downstream pathways, regardless of mu opioid receptor activation.

Tolerance and overdoses

Opioid overdoses kill through apnea

Apnea

Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...

 and fatal hypoxia

Hypoxia (medical)

Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

, often
aggravated by simultaneous use of alcohol

Alcohol

In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

, benzodiazepines or barbiturates. Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses (an example of Mithridatism

Mithridatism

Mithridatism is the practice of protecting oneself against a poison by gradually self-administering non-lethal amounts. The word derives from Mithridates VI, the King of Pontus, who so feared being poisoned that he regularly ingested small doses, aiming to develop immunity...

). However tolerance to respiratory depression is lost just as quickly during withdrawal. Many overdoses occur in people who misuse their medication after being in withdrawal long enough to lose the tolerance to respiratory depression. Less commonly, massive overdoses have been known to cause circulatory collapse

Circulatory collapse

A circulatory collapse is defined as a general or specific failure of the circulation, either cardiac or peripheral in nature. A common cause of this could be shock or trauma from injury or surgery...

.

Opioid overdoses can be rapidly reversed with any of several opioid antagonists

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

: naloxone

Naloxone

Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

, or naltrexone

Naltrexone

Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...

, differing primarily in their duration of action and potency. While commonly referred to as antagonists, and when used to treat an overdose they do appear to function as such, naloxone & naltrexone are inverse agonist

Inverse agonist

In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....

s.

External links