Opioid receptor
Encyclopedia
Opioid receptors are a group of G protein-coupled receptor
s with opioid
s as ligands
. The endogenous
opioids are dynorphin
s, enkephalin
s, endorphin
s, endomorphin
s and nociceptin
. The opioid receptors are ~40% identical to somatostatin
receptor
s (SSTRs). Opiate receptors are distributed widely in the brain
, and are found in the spinal cord
and digestive tract
.
drugs were likely to exert their actions at specific receptor sites, and that there were likely to be multiple such sites. Early studies had indicated that opiates appeared to accumulate in the brain. The receptors were first identified as specific molecules through the use of binding studies, in which opiates that had been labeled with radioisotopes
were found to bind to brain membrane
homogenates. The first such study was published in 1971, using 3H
-levorphanol
. In 1973, Candace Pert
and Solomon H. Snyder
published the first detailed binding study of what would turn out to be the μ opioid receptor, using 3H
-naloxone
. That study has been widely credited as the first definitive finding of an opioid receptor, although two other studies followed shortly after.
-chlornaltrexamine
.
(I). Name based on order of discovery
that was found to bind to them. Morphine
was the first chemical shown to bind to mu receptors. The first letter of the drug morphine is m, but in biochemistry there is a tendency to use Greek letters, thus turning the m to μ. In similar manner, a drug known as ketocyclazocine was first shown to attach itself to κ receptors, while the δ receptor was named after the mouse vas deferens
tissue in which the receptor was first characterised. An additional opioid receptor was later identified and cloned based on homology with the cDNA. This receptor is known as the nociceptin receptor
or ORL 1 receptor.
The opioid receptor types are ~70% identical with differences located at N and C termini. The μ receptor is perhaps the most important. It is thought that the G protein
binds to the third intracellular loop of the opioid receptors. Both in mice and human
s, the genes for the various receptor subtypes are located on different chromosomes.
Separate subtypes have been identified in human tissue. Research has so far failed to identify the genetic evidence of the subtypes, and it is thought that they arise from post-translational modification of cloned receptor types.
An IUPHAR
subcommittee has recommended that appropriate terminology for the 3 classical (μ, δ, κ) receptors, and the non-classical (nociceptin) receptor, should be MOP, DOP, KOP and NOP respectively.
were once considered to be opioid receptors due to the antitussive actions of many opioid drugs' being mediated via σ receptors, and the first selective σ agonists being derivatives of opioid drugs (e.g., allylnormetazocine
). However, σ receptors were found to not be activated by endogenous opioid peptides, and are quite different from the other opioid receptors in both function and gene sequence, so they are now not usually classified with the opioid receptors.
The existence of further opioid receptors has also been suggested, due to pharmacological evidence of actions produced by endogenous opioid peptides but shown not to be mediated through any of the four known opioid receptor subtypes. The only one of these additional receptors to have been definitively identified is the zeta (ζ) opioid receptor, which has been shown to be a cellular growth factor modulator with met-enkephalin
being the endogenous ligand. This receptor is now most commonly referred to as the opioid growth factor receptor (OGFr)
.
Another postulated opioid receptor is the ε opioid receptor. The existence of this receptor was suspected after the endogenous opioid peptide beta-endorphin
was shown to produce additional actions that did not seem to be mediated through any of the known opioid receptors. Activation of this receptor produces strong analgesia and release of met-enkephalin, and a number of widely used opioid agonists such as the μ agonist etorphine
and the κ agonist bremazocine
have been shown to act as agonists for this effect (even in the presence of antagonists to their more well known targets), while buprenorphine
has been shown to act as an epsilon antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor, however efforts to locate a gene for this receptor have been unsuccessful, and epsilon-mediated effects were absent in μ/δ/κ "triple knockout" mice
, suggesting the epsilon receptor is likely to be either a splice variant derived from alternate post-translational modification, or a heteromer
derived from hybridization of two or more of the known opioid receptors.
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 with 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...
s as ligands
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...
. The 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...
opioids are 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, 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, endorphin
Endorphin
Endorphins are endogenous opioid peptides that function as neurotransmitters. They are produced by the pituitary gland and the hypothalamus in vertebrates during exercise, excitement, pain, consumption of spicy food, love and orgasm, and they resemble the opiates in their abilities to produce...
s, endomorphin
Endomorphin
Endomorphins are two endogenous opioid peptides. Endomorphin-1 and endomorphin-2 are tetrapeptides with the highest known affinity and specificity for the μ opioid receptor...
s and nociceptin
Nociceptin
Nociceptin or orphanin FQ, a 17 amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor . It is derived from the prepronociceptin protein, as are a further 2 peptides, nocistatin & NocII...
. The opioid receptors are ~40% identical to somatostatin
Somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s (SSTRs). Opiate receptors are distributed widely in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, and are found in 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...
and digestive tract
Digestion
Digestion is the mechanical and chemical breakdown of food into smaller components that are more easily absorbed into a blood stream, for instance. Digestion is a form of catabolism: a breakdown of large food molecules to smaller ones....
.
Discovery
By the mid-1960s, it had become apparent from pharmacologic studies that opiateOpiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
drugs were likely to exert their actions at specific receptor sites, and that there were likely to be multiple such sites. Early studies had indicated that opiates appeared to accumulate in the brain. The receptors were first identified as specific molecules through the use of binding studies, in which opiates that had been labeled with radioisotopes
Radionuclide
A radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to be imparted either to a newly created radiation particle within the nucleus or to an atomic electron. The radionuclide, in this process, undergoes radioactive decay, and emits gamma...
were found to bind to brain membrane
Biological membrane
A biological membrane or biomembrane is an enclosing or separatingmembrane that acts as a selective barrier, within or around a cell. It consists of a lipid bilayer with embedded proteins that may constitute close to 50% of membrane content...
homogenates. The first such study was published in 1971, using 3H
Tritium
Tritium is a radioactive isotope of hydrogen. The nucleus of tritium contains one proton and two neutrons, whereas the nucleus of protium contains one proton and no neutrons...
-levorphanol
Levorphanol
Levorphanol is an opioid medication used to treat severe pain. It is the levorotatory stereoisomer of the synthetic morphinan and a pure opioid agonist, first described in Germany in 1948 as an orally active morphine-like analgesic...
. In 1973, Candace Pert
Candace Pert
Candace Beebe Pert is an American neuroscientist and pharmacologist who discovered the opiate receptor, the cellular binding site for endorphins in the brain.-History:...
and Solomon H. Snyder
Solomon H. Snyder
Solomon H. Snyder is an American neuroscientist.Snyder attended Georgetown University 1955-1958 and received his MD from Georgetown University School of Medicine in 1962. After medical internship at the Kaiser Hospital in San Francisco, he served as a research associate 1963-1965 at the NIH,...
published the first detailed binding study of what would turn out to be the μ opioid receptor, using 3H
Tritium
Tritium is a radioactive isotope of hydrogen. The nucleus of tritium contains one proton and two neutrons, whereas the nucleus of protium contains one proton and no neutrons...
-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...
. That study has been widely credited as the first definitive finding of an opioid receptor, although two other studies followed shortly after.
Purification
Purification of the receptor further verified its existence. The first attempt to purify the receptor involved the use of a novel opioid receptor antagonist called chlornaltrexamine that was demonstrated to bind to the opioid receptor Caruso et al., 1980 purified the detergent-extracted component of rat brain membrane that eluted with the specifically bound 3HTritium
Tritium is a radioactive isotope of hydrogen. The nucleus of tritium contains one proton and two neutrons, whereas the nucleus of protium contains one proton and no neutrons...
-chlornaltrexamine
Chlornaltrexamine
Chlornaltrexamine is an irreversible mixed agonist-antagonist for μ-opioid receptors, which forms a covalent bond to the active site. It is 22 times more potent than morphine...
.
Major subtypes
There are four major subtypes of opioid receptors:| Receptor | Subtypes | Location | >- | δ1, δ2 |
|
κ1, κ2, κ3 |
|
μ1, μ2, μ3 |
|
μ1:
Physical dependence Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction... μ2:
μ3:
>- | Nociceptin receptor Nociceptin receptor The nociceptin receptor or NOP also known as the orphanin FQ receptor or kappa-type 3 opioid receptor is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a G protein-coupled receptor whose natural ligand is known as nociceptin or orphanin FQ, a 17 amino acid... OP4 |
ORL1 |
|
|
|---|
(I). Name based on order of discovery
Naming
The receptors were named using the first letter of the first ligandLigand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
that was found to bind to them. 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...
was the first chemical shown to bind to mu receptors. The first letter of the drug morphine is m, but in biochemistry there is a tendency to use Greek letters, thus turning the m to μ. In similar manner, a drug known as ketocyclazocine was first shown to attach itself to κ receptors, while the δ receptor was named after the mouse vas deferens
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
tissue in which the receptor was first characterised. An additional opioid receptor was later identified and cloned based on homology with the cDNA. This receptor is known as the nociceptin receptor
Nociceptin receptor
The nociceptin receptor or NOP also known as the orphanin FQ receptor or kappa-type 3 opioid receptor is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a G protein-coupled receptor whose natural ligand is known as nociceptin or orphanin FQ, a 17 amino acid...
or ORL 1 receptor.
The opioid receptor types are ~70% identical with differences located at N and C termini. The μ receptor is perhaps the most important. It is thought that the G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
binds to the third intracellular loop of the opioid receptors. Both in mice and human
Human
Humans are the only living species in the Homo genus...
s, the genes for the various receptor subtypes are located on different chromosomes.
Separate subtypes have been identified in human tissue. Research has so far failed to identify the genetic evidence of the subtypes, and it is thought that they arise from post-translational modification of cloned receptor types.
An IUPHAR
International Union of Basic and Clinical Pharmacology
The International Union of Basic and Clinical Pharmacology is a voluntary, non-profit association representing the interests of scientists in pharmacology-related fields to facilitate Better Medicines through Global Education and Research around the world.-History:Established in 1959 as a section...
subcommittee has recommended that appropriate terminology for the 3 classical (μ, δ, κ) receptors, and the non-classical (nociceptin) receptor, should be MOP, DOP, KOP and NOP respectively.
Additional receptors
σ receptorsSigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
were once considered to be opioid receptors due to the antitussive actions of many opioid drugs' being mediated via σ receptors, and the first selective σ agonists being derivatives of opioid drugs (e.g., allylnormetazocine
Allylnormetazocine
Alazocine , or -N-allylnormetazocine , was the first drug discovered to act as a σ1 receptor agonist . It has no significant affinity for the σ2 receptor. Alazocine also acts as a κ-opioid receptor agonist , and to a much lesser extent, as an NMDA receptor antagonist ....
). However, σ receptors were found to not be activated by endogenous opioid peptides, and are quite different from the other opioid receptors in both function and gene sequence, so they are now not usually classified with the opioid receptors.
The existence of further opioid receptors has also been suggested, due to pharmacological evidence of actions produced by endogenous opioid peptides but shown not to be mediated through any of the four known opioid receptor subtypes. The only one of these additional receptors to have been definitively identified is the zeta (ζ) opioid receptor, which has been shown to be a cellular growth factor modulator with met-enkephalin
Met-enkephalin
[Met]enkephalin, sometimes referred to as opioid growth factor , is a naturally-occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being [leu]enkephalin...
being the endogenous ligand. This receptor is now most commonly referred to as the opioid growth factor receptor (OGFr)
OGFR
Opioid growth factor receptor, also known as OGFr or the ζ-opioid receptor, is a protein which in humans is encoded by the OGFR gene. The protein encoded by this gene is a receptor for opioid growth factor , also known as [Met]-enkephalin...
.
Another postulated opioid receptor is the ε opioid receptor. The existence of this receptor was suspected after the endogenous opioid peptide 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:...
was shown to produce additional actions that did not seem to be mediated through any of the known opioid receptors. Activation of this receptor produces strong analgesia and release of met-enkephalin, and a number of widely used opioid agonists such as the μ agonist etorphine
Etorphine
Etorphine is a semi-synthetic opioid possessing an analgesic potency approximately 200 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather in "poppy straw" and in related plants, Papaver orientale and Papaver...
and the κ agonist bremazocine
Bremazocine
Bremazocine is a κ-opioid receptor agonist related to pentazocine. It has potency and long-lasting analgesic and diuretic effects....
have been shown to act as agonists for this effect (even in the presence of antagonists to their more well known targets), while buprenorphine
Buprenorphine
Buprenorphine is a semi-synthetic opioid that is used...
has been shown to act as an epsilon antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor, however efforts to locate a gene for this receptor have been unsuccessful, and epsilon-mediated effects were absent in μ/δ/κ "triple knockout" mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
, suggesting the epsilon receptor is likely to be either a splice variant derived from alternate post-translational modification, or a heteromer
Heteromer
-Pharmacology:* Ligand-gated ion channels such as the nicotinic acetylcholine receptor and GABAA receptor are composed of five subunits arranged around a central pore that opens to allow ions to pass through. There are a large number of different subunits available, which can come together in a...
derived from hybridization of two or more of the known opioid receptors.