Opioid receptors are a group of G-protein coupled receptors with
opioidAn opioid is a chemical that works by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract...
s as
ligandIn chemistry, a ligand is either an atom, ion, or molecule that binds to a central metal-atom to produce a coordination complex. The bonding between the metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The metal-ligand bonding ranges from covalent...
s. The
endogenousThe word endogenous means "proceeding from within", the opposite of exogenous.-Biology:Endogenous substances are those that originate from within an organism, tissue, or cell . Endogenous retrovirus are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
opioids are
dynorphinDynorphins 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,
enkephalinAn 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,
endorphinEndorphins are endogenous opioid polypeptide compounds. They are produced by the pituitary gland and the hypothalamus in vertebrates during strenuous exercise, excitement, pain and orgasm, and they resemble the opiates in their abilities to produce analgesia and a feeling of well-being. Endorphins...
s,
endomorphinEndomorphins 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
nociceptinNociceptin 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
somatostatinSomatostatin 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...
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
s (SSTRs).
By the mid-1960s, it had become apparent from pharmacologic studies that
opiateIn medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant, as well as many semisynthetic chemical derivatives of such alkaloids.-Overview:...
drugs were likely to exert their actions at specific receptor sites, and that there were likely to be multiple such sites. The receptors were first identified as specific molecules through the use of binding studies, in which opiates that had been labeled with
radioisotopesA radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy which is available to be imparted either to a newly-created radiation particle within the nucleus, or else to an atomic electron . The radionuclide, in this process, undergoes radioactive decay,...
were found to bind to brain
membraneA biological membrane or biomembrane is an enclosing or separating amphipathic layer that acts as a barrier within or around a cell. It is almost invariably a lipid bilayer, composed of a double layer of lipid molecules and proteins that may constitute close to 50% of membrane...
homogenates.
Opioid receptors are a group of G-protein coupled receptors with
opioidAn opioid is a chemical that works by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract...
s as
ligandIn chemistry, a ligand is either an atom, ion, or molecule that binds to a central metal-atom to produce a coordination complex. The bonding between the metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The metal-ligand bonding ranges from covalent...
s. The
endogenousThe word endogenous means "proceeding from within", the opposite of exogenous.-Biology:Endogenous substances are those that originate from within an organism, tissue, or cell . Endogenous retrovirus are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
opioids are
dynorphinDynorphins 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,
enkephalinAn 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,
endorphinEndorphins are endogenous opioid polypeptide compounds. They are produced by the pituitary gland and the hypothalamus in vertebrates during strenuous exercise, excitement, pain and orgasm, and they resemble the opiates in their abilities to produce analgesia and a feeling of well-being. Endorphins...
s,
endomorphinEndomorphins 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
nociceptinNociceptin 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
somatostatinSomatostatin 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...
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
s (SSTRs).
Discovery
By the mid-1960s, it had become apparent from pharmacologic studies that
opiateIn medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant, as well as many semisynthetic chemical derivatives of such alkaloids.-Overview:...
drugs were likely to exert their actions at specific receptor sites, and that there were likely to be multiple such sites. The receptors were first identified as specific molecules through the use of binding studies, in which opiates that had been labeled with
radioisotopesA radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy which is available to be imparted either to a newly-created radiation particle within the nucleus, or else to an atomic electron . The radionuclide, in this process, undergoes radioactive decay,...
were found to bind to brain
membraneA biological membrane or biomembrane is an enclosing or separating amphipathic layer that acts as a barrier within or around a cell. It is almost invariably a lipid bilayer, composed of a double layer of lipid molecules and proteins that may constitute close to 50% of membrane...
homogenates. The first such study was published in 1971, using
3HTritium 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...
-
levorphanolLevorphanol is an opioid medication used to treat severe pain. It is the laevorotary stereoisomer of the synthetic morphinan and a pure opioid agonist, first described in Germany in 1946 as an orally active morphine-like analgesic...
. In 1973,
Candace PertCandace Beebe Pert is an American neuroscientist and pharmacologist who discovered the opiate receptor, the cellular binding site for endorphins in the brain. In 1974 she earned a Ph.D. in pharmacology from Johns Hopkins University School of Medicine, where she worked in the laboratory of Solomon...
and
Solomon H. SnyderSolomon H. Snyder is an American neuroscientist.Snyder graduated from Georgetown University in 1958 and Georgetown University Medical Center in 1962. At a very early age he published research on ornithine decarboxylase and RNA synthesis...
published the first detailed binding study of what would turn out to be the μ opioid receptor, using
3HTritium 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...
-
naloxoneNaloxone is a drug used to counter the effects of opioid overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory system. Naloxone is also experimentally used in the treatment for CIPA;...
. That study has been widely credited as the first definitive finding of an opioid receptor, although two other studies followed shortly after.
Major subtypes
There are four major subtypes of opioid receptors:
| Receptor |
Subtypes |
Location |
|
>-
| delta (δ)The δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as their endogenous ligands.-Function:...
OP1 (I)
δ1, δ2 |
- Brain
The brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
- pontine
The pons is a structure located on the brain stem. It is cranial to the medulla oblongata, caudal to the midbrain, and ventral to the cerebellum...
nuclei
- amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans...
- olfactory bulbs
- deep cortex
The cerebral cortex is a structure within the brain that plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It constitutes the outermost layer of the cerebrum. In preserved brains, it has a grey color, hence the name "grey matter"...
|
analgesia
antidepressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia. Drugs including the monoamine oxidase inhibitors , tricyclic antidepressants , tetracyclic antidepressants , selective serotonin reuptake inhibitors , and serotonin-norepinephrine...
effects
physical dependencePhysical 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. Physical dependence can develop from low-dose therapeutic use of certain medications as...
>-
| kappa (κ)The κ-Opioid receptor is a type of opioid receptor which binds the peptide opioid dynorphin as the primary endogenous ligand. κ receptors are widely distributed in the brain, spinal cord, and in pain neurons.-Receptor subtypes:...
OP2 (I)
κ1, κ2, κ3 |
- Brain
The brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
- hypothalamus
The hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland ....
- periaqueductal gray
Periaqueductal gray is the gray matter located around the cerebral aqueduct within the midbrain. It plays a role in the descending modulation of pain and in defensive behaviour. The ascending pain and temperature fibers of the spinothalamic tract also send information to the PAG via the...
- claustrum
The claustrum, which is suspected to be present in all mammals, is a fairly thin vertical curved sheet of subcortical gray matter...
- 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 around 45 cm long in men and around 43 cm long in women. The length of the spinal cord is much shorter than...
- substantia gelatinosa
Substantia gelatinosa can refer to:* Substantia gelatinosa of Rolando * Substantia gelatinosa centralisSubstantia gelatinosa is a structure involved in pain transmission....
|
Spinal analgesia
sedationSedation is a medical procedure involving the administration of sedative drugs, generally to facilitate a medical procedure with local anaesthesia.- Uses :...
miosisMiosis is constriction of the pupil of the eye. This is a normal response to an increase in light but can also be associated with certain pathological conditions, microwave radiation exposure, and certain drugs, especially opiates....
inhibition of ADH release
>-
| mu (μ)The μ opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
OP3 (I)
μ1, μ2, μ3 |
- Brain
The brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
- cortex
The cerebral cortex is a structure within the brain that plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It constitutes the outermost layer of the cerebrum. In preserved brains, it has a grey color, hence the name "grey matter"...
(laminae III and IV)
- thalamus
The thalamus is a midline paired symmetrical structure within the brain of vertebrate animals, including humans. It is between the cerebral cortex and the midbrain, both in terms of its location and its neurological connections...
- striosomes
- periaqueductal gray
Periaqueductal gray is the gray matter located around the cerebral aqueduct within the midbrain. It plays a role in the descending modulation of pain and in defensive behaviour. The ascending pain and temperature fibers of the spinothalamic tract also send information to the PAG via the...
- 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 around 45 cm long in men and around 43 cm long in women. The length of the spinal cord is much shorter than...
- substantia gelatinosa
Substantia gelatinosa can refer to:* Substantia gelatinosa of Rolando * Substantia gelatinosa centralisSubstantia gelatinosa is a structure involved in pain transmission....
|
μ1:
Supraspinal Supraspinal means above the spine, and may refer to,above the spinal cord and vertebral column:*brainor above the spine of scapula:*supraspinatus muscle*supraspinatous fascia*supraspinatous fossa*supraspinous ligament...
analgesia
physical dependencePhysical 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. Physical dependence can develop from low-dose therapeutic use of certain medications as...
μ2:
- respiratory depression
- miosis
Miosis is constriction of the pupil of the eye. This is a normal response to an increase in light but can also be associated with certain pathological conditions, microwave radiation exposure, and certain drugs, especially opiates....
- euphoria
Euphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria or euphoric may also refer to:* Euphoria , genus of scarab beetles...
- reduced GI
The human gastrointestinal tract , digestive tract, guts or gut is the system of organs within humans that takes in food, digests it to extract energy and nutrients, and expels the remaining matter...
motility
- 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. Physical dependence can develop from low-dose therapeutic use of certain medications as...
>-
| Nociceptin receptorAn additional opioid receptor has been identified and cloned based on homology with the cDNA. This receptor is known as the nociceptin receptor or NOP receptor...
OP4 |
ORL1 |
- Brain
The brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
- cortex
Cortex may mean any of the following:In anatomy:* Cortex , the outermost or superficial layer of an organ, and especially in the brain:...
- amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans...
- hippocampus
The hippocampus is a major component of the brains of humans and other mammals. It belongs to the limbic system and plays important roles in long-term memory and spatial navigation. Like the cerebral cortex, with which it is closely associated, it is a paired structure, with mirror-image halves in...
- septal nuclei
The septal nuclei are structures in the middle anteroventral cerebrum that are composed of medium-size neurons grouped into medial, lateral, and posterior groups...
- habenula
In neuroanatomy, habenula originally denoted the stalk of the pineal gland , but gradually came to refer to a neighboring group of nerve cells with which the pineal gland was believed to be associated, the habenular nucleus...
- hypothalamus
The hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland ....
- spinal cord
|
anxiety
depression
appetite
development of tolerance to μ agonists |
(I). Name based on order of discovery
The receptors were named using the first letter of the first
ligandIn chemistry, a ligand is either an atom, ion, or molecule that binds to a central metal-atom to produce a coordination complex. The bonding between the metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The metal-ligand bonding ranges from covalent...
that was found to bind to them.
MorphineMorphine is a highly potent opiate analgesic psychoactive drug, is the principal active ingredient in Papaver somniferum , is considered to be the prototypical opioid. Like other opioids, e.g...
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. Similarly a drug known as ketocyclazocine was first shown to attach itself to kappa receptors, while the delta receptor was named after the mouse
vas deferensThe vas deferens , also called ductus deferens, , is part of the male anatomy of some species; they transport sperm from the epididymis in anticipation of ejaculation.-Structure:...
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 receptorAn additional opioid receptor has been identified and cloned based on homology with the cDNA. This receptor is known as the nociceptin receptor or NOP receptor...
or ORL 1 receptor.
The opioid receptor types are ~70% identical with differences located at N and C termini. The μ receptor (the μ represents morphine) is perhaps the most important. It is thought that the
G proteinG proteins, short for guanine nucleotide-binding proteins, are a family of proteins involved in second messenger cascades.G proteins are so called because they function as "molecular switches," alternating between an inactive guanosine diphosphate and active guanosine triphosphate bound state,...
binds to the third intracellular loop of the opioid receptors. Both in mice and
humanHumans are bipedal primates belonging to the species Homo sapiens in Hominidae, the great ape family. They are the only surviving member of the genus Homo. Humans have a highly developed brain, capable of abstract reasoning, language, introspection, and problem solving...
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
IUPHARThe 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
Sigma receptorThe sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, Ditolylguanidine, Dimethyltryptamine and siramesine.-Classification:...
s (σ) were once considered to be opioid receptors due to the antitussive actions of many opioid drugs being mediated via sigma receptors, and the first selective sigma agonists being derivatives of opioid drugs (e.g.
allylnormetazocineAlazocine , or N-allylnormetazocine , was the first drug discovered to act as a sigma receptor agonist. It also acts as a kappa-Opioid receptor agonist, among other effects. Alazocine is related to pentazocine....
), however sigma 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-enkephalinMet-enkephalin is an endogenous opioid peptide neurotransmitter found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is leu-enkephalin. The tyrosine residue at position 1 is thought to be analogous to the 3-hydroxyl group on morphine....
being the endogenous ligand. This receptor is now most commonly referred to as the
opioid growth factor receptor (OGFr)Opioid growth factor receptor, also known as OGFr or the zeta 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 putative opioid receptor is the epsilon (ε) opioid receptor. The existence of this receptor was suspected after the endogenous opioid peptide
beta-endorphinBeta-endorphin is an endogenous opioid peptide neurotransmitter found in the neurons of both the central and peripheral nervous system.Sequence:...
was shown to produce additional actions which 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
etorphineEtorphine is a semi-synthetic opioid possessing an analgesic potency approximately 1,000-3,000 times that of morphine depending on the situation. 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,...
and the κ agonist
bremazocineBremazocine is a kappa-Opioid receptor agonist related to pentazocine. It has potent 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
buprenorphineBuprenorphine is a semi-synthetic opiate with partial agonist and antagonist actions. Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman as an analgesic, available generally as Temgesic 0.2 mg sublingual tablets, and as Buprenex in a 0.3 mg/ml injectable...
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" miceA knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. Knockout mice are important animal models for studying the role of genes which have been sequenced, but have unknown functions...
, suggesting the epsilon receptor is likely to be either a splice variant derived from alternate post-translational modification, or a
heteromerA heteromer is something that consists of parts of different chemical composition. Examples are:-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...
derived from hybridization of two or more of the known opioid receptors.
Pathology
Some forms of mutations in δ-opioid receptors have resulted in constant receptor activation.
External links