Kappa Opioid receptor
Encyclopedia
The κ-opioid receptor (KOR) is a protein
that in humans is encoded by the OPRK1 gene
. The κ-opioid receptor is one of five related receptors
that bind opium
-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering the perception of pain, consciousness, motor control, and mood.
The κ-opioid receptor is a type of opioid receptor
that binds the opioid
peptide
dynorphin
as the primary endogenous ligand
. In addition to dynorphin, a variety of natural alkaloid
s and synthetic ligands bind to the receptor. The κ-opioid receptor may provide a natural addiction control mechanism, and consequently selective agonists of this receptor may have therapeutic potential in the treatment of addiction.
(hypothalamus
, periaqueductal gray
, and claustrum
), spinal cord
(substantia gelatinosa
), and in pain neuron
s.
clone has been identified, hence these receptor subtypes likely arise from interaction of one κ-opioid receptor protein with other membrane associated proteins.
but dysphoria from κ-opioid receptor agonists has been shown to differ between the sexes. More recent studies have shown the aversive properties in a variety of ways and the κ-opioid receptor has been strongly implicated as an integral neurochemical component of addiction and the remission thereof.
It is now widely accepted that κ-opioid receptor (partial) agonists have dissociative and deliriant
effects, as exemplified by salvinorin A
. These effects are generally undesirable in medicinal drugs and could have had frightening or disturbing effects in the tested humans. It is thought that the hallucinogenic effects of drugs such as butorphanol
, nalbuphine
, and pentazocine
serve to limit their opiate abuse potential. In the case of salvinorin A, a structurally novel neoclerodane diterpene
κ-opioid receptor agonist, these hallucinogenic, more specifically deliriant and dissociative, effects are sought after, even though the experience is often considered dysphoric by the user. While salvinorin A is considered a hallucinogen, it is not a psychedelic, and its effects are qualitatively different than those produced by the classical psychedelic
hallucinogens such as LSD
or mescaline
.
The involvement of the κ-opioid receptor in stress response has been elucidated.
Activation of the κ-opioid receptor appears to antagonize many of the effects of the μ-opioid receptor
.
κ-Opioid receptor ligands are also known for their characteristic diuretic
effects, due to their negative regulation of antidiuretic hormone (ADH).
κ-Opioid agonism is neuroprotective against hypoxia
/ischemia
; as such, κ-opioid receptors may represent a novel therapeutic target.
Gi/G0
, which subsequently increases phosphodiesterase
activity. Phosphodiesterases break down cAMP
, producing an inhibitory effect in neurons. κ-Opioid receptors also couple to inward-rectifier potassium
and to N-type calcium
ion channels. Recent studies have also demonstrated that agonist-induced stimulation of the κ-Opioid receptor, like other G-protein coupled receptors, can result in the activation of mitogen-activated protein kinases (MAPK). These include extracellular signal-regulated kinase, p38 MAP kinases, and c-Jun N-terminal kinases
.
and terpenoid natural product salvinorin A
are potent and selective κ-opioid receptor agonist
s. The κ-opioid receptor also mediates the action of the hallucinogenic side effects of opioid
s such as pentazocine
.
, spearmint
, and watermint), the naturally-occurring compound Menthol
is a weak k-opioid receptor agonist owing to its antinociceptive effects in rats. In addition, mints can desensitize a region through the activation of TRPM8
receptors (the 'cold'/menthol receptor).
, Salvinorin A
, is known as a non-toxic yet potent κ-opioid agonist.
One area of the brain most strongly associated with addiction is the nucleus accumbens
(NAcc) and striatum
while other structures that project to and from the NAcc also play a critical role. Though many other changes occur, addiction is often characterized by the reduction of dopamine D2 receptors
in the NAcc. In addition to low NAcc D2 binding, cocaine is also known to produce a variety of changes to the primate brain such as increases prodynorphin mRNA in caudate putamen (striatum) and decreases of the same in the hypothalamus
while the administration of a κ-opioid agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.
Additionally, while cocaine overdose victims showed a large increase in κ-opioid receptors (doubled) in the NAcc, κ-opioid agonist administration is shown to be effective in decreasing cocaine seeking and self-administration. Furthermore, while cocaine abuse is associated with lowered prolactin response, κ-opioid activation causes a release in prolactin
, a hormone known for its important role in learning, neuronal plasticity and myelination.
It has also been reported that the κ-opioid system is critical for stress-induced drug-seeking. In animal models, stress has been demonstrated to potentiate cocaine reward behavior in a kappa opioid-dependent manner. These effects are likely caused by stress-induced drug craving that requires activation of the κ-opioid system. Although seemingly paradoxical, it is well known that drug taking results in a change from homeostasis
to allostasis
. It has been suggested that withdrawal-induced dysphoria or stress-induced dysphoria may act as a driving force by which the individual seeks alleviation via drug taking The rewarding properties of drug are altered, and it is clear κ-opioid activation following stress modulates the valence of drug to increase its rewarding properties and cause potentiation of reward behavior, or reinstatement to drug seeking. The stress-induced activation of κ-opioid receptors is likely due to multiple signaling mechanisms. The effects of κ-opioid agonism on dopamine systems are well documented, and recent work also implicates the mitogen-activated protein kinase cascade and pCREB in κ-opioid dependent behaviors.
Though cocaine abuse is a frequently used model of addiction, κ-opioid agonists have very marked effects on all types of addiction including alcohol and opiate abuse. Not only are genetic differences in dynorphin receptor expression a marker for alcohol dependence but a single dose of a κ-opioid antagonist markedly increased alcohol consumption in lab animals. There are numerous studies that reflect a reduction in self-administration of alcohol, and heroin dependence has also been shown to be effectively treated with κ-opioid agonism by reducing the immediate rewarding effects and by causing the curative effect of up-regulation of μ-opioid receptors that have been down-regulated during opioid abuse.
The anti-rewarding properties of κ-opioid agonists are mediated through both long-term and short-term effects. The immediate effect of κ-opioid agonism leads to reduction of dopamine release in the NAcc during self administration of cocaine and over the long term up-regulates receptors that have been down-regulated during substance abuse such as μ-opioid and D2 receptors. These receptors modulate the release of other neurochemical
s such as serotonin
in the case of μ-opioid receptor agonists and acetylcholine in the case of D2. These changes can account for the physical and psychological remission of the pathology of addiction. The longer effects of κ-opioid agonism (30 minutes or greater) have been linked to κ-opioid receptor-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by κ-opioid-dependent modulation of dopamine
, serotonin
, or norepinephrine
and/or via activation of downstream signal transduction pathways.
with Sodium-hydrogen antiporter 3 regulator 1
and Ubiquitin C
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the OPRK1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The κ-opioid receptor is one of five related receptors
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...
that bind 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...
-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering the perception of pain, consciousness, motor control, and mood.
The κ-opioid receptor is a type 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...
that binds the 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...
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...
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...
as the primary 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...
. In addition to dynorphin, a variety of natural 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 and synthetic ligands bind to the receptor. The κ-opioid receptor may provide a natural addiction control mechanism, and consequently selective agonists of this receptor may have therapeutic potential in the treatment of addiction.
Distribution
κ-Opioid receptors are widely distributed in the brainBrain
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,...
(hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, 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...
, and claustrum
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
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...
(substantia gelatinosa
Substantia gelatinosa
Substantia gelatinosa can refer to:* Substantia gelatinosa of Rolando * Substantia gelatinosa centralisSubstantia gelatinosa is a structure involved in pain transmission....
), and in pain neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s.
Subtypes
Based on receptor binding studies, three variants of the κ-opioid receptor designated κ1, κ2, and κ3 have been characterized. However only one cDNAComplementary DNA
In genetics, complementary DNA is DNA synthesized from a messenger RNA template in a reaction catalyzed by the enzyme reverse transcriptase and the enzyme DNA polymerase. cDNA is often used to clone eukaryotic genes in prokaryotes...
clone has been identified, hence these receptor subtypes likely arise from interaction of one κ-opioid receptor protein with other membrane associated proteins.
Function
It has long been understood that κ-opioid receptor agonists are dysphoricDysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
but dysphoria from κ-opioid receptor agonists has been shown to differ between the sexes. More recent studies have shown the aversive properties in a variety of ways and the κ-opioid receptor has been strongly implicated as an integral neurochemical component of addiction and the remission thereof.
It is now widely accepted that κ-opioid receptor (partial) agonists have dissociative and deliriant
Deliriant
The deliriants are a special class of acetylcholine-inhibitor hallucinogen. The term was introduced by David F. Duncan and Robert S...
effects, as exemplified by salvinorin A
Salvinorin A
Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans...
. These effects are generally undesirable in medicinal drugs and could have had frightening or disturbing effects in the tested humans. It is thought that the hallucinogenic effects of drugs such as butorphanol
Butorphanol
Butorphanol is a morphinan-type synthetic opioid analgesic developed by Bristol-Myers. Brand name Stadol was recently discontinued by the manufacturer. It is now only available in its generic formulations, manufactured by Novex, Mylan, Apotex and Ben Venue Laboratories. Butorphanol is most...
, nalbuphine
Nalbuphine
Nalbuphine is a semi-synthetic opioid used commercially as an analgesic under a variety of trade names, including Nubain. It is noteworthy in part for the fact that at low dosages, it is found much more effective by women than by men, and may even increase pain in men, leading to its...
, and pentazocine
Pentazocine
Pentazocine is a synthetically prepared prototypical mixed agonist-antagonist narcotic drug of the benzomorphan class of opioids used to treat moderate to moderately severe pain...
serve to limit their opiate abuse potential. In the case of salvinorin A, a structurally novel neoclerodane diterpene
Diterpene
Diterpenes are a type of terpenes composed of four isoprene units. They derive from geranylgeranyl pyrophosphate. Diterpenes form the basis for biologically important compounds such as retinol, retinal, and phytol...
κ-opioid receptor agonist, these hallucinogenic, more specifically deliriant and dissociative, effects are sought after, even though the experience is often considered dysphoric by the user. While salvinorin A is considered a hallucinogen, it is not a psychedelic, and its effects are qualitatively different than those produced by the classical psychedelic
Psychedelic
The term psychedelic is derived from the Greek words ψυχή and δηλοῦν , translating to "soul-manifesting". A psychedelic experience is characterized by the striking perception of aspects of one's mind previously unknown, or by the creative exuberance of the mind liberated from its ostensibly...
hallucinogens such as LSD
LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
or mescaline
Mescaline
Mescaline or 3,4,5-trimethoxyphenethylamine is a naturally occurring psychedelic alkaloid of the phenethylamine class used mainly as an entheogen....
.
The involvement of the κ-opioid receptor in stress response has been elucidated.
Activation of the κ-opioid receptor appears to antagonize many of the effects of the μ-opioid receptor
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
.
κ-Opioid receptor ligands are also known for their characteristic diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
effects, due to their negative regulation of antidiuretic hormone (ADH).
κ-Opioid agonism is neuroprotective against 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...
/ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
; as such, κ-opioid receptors may represent a novel therapeutic target.
Signal transduction
κ-Opioid receptor activation by agonists is coupled to the G proteinG 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...
Gi/G0
Gi alpha subunit
Gi alpha subunit is a heterotrimeric G protein subunit that inhibits the production of cAMP from ATP.- Receptors :The following G protein-coupled receptors couple to the Gi subunit:* Acetylcholine M2 & M4 receptors...
, which subsequently increases phosphodiesterase
Phosphodiesterase
A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
activity. Phosphodiesterases break down cAMP
CAMP
CAMP may stand for:* Cyclic adenosine monophosphate * Cathelicidin, or Cathelicidin antimicrobial peptide* Campaign Against Marijuana Planting* Central Atlantic Magmatic Province* CAMP , an Italian manufacturer of climbing equipment...
, producing an inhibitory effect in neurons. κ-Opioid receptors also couple to inward-rectifier potassium
Inward-rectifier potassium ion channel
Inwardly rectifying potassium channels are a specific subset of potassium selective ion channels. To date, seven subfamilies have been identified in various mammalian cell types...
and to N-type calcium
N-type calcium channel
The N-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit forms the pore through which calcium enters the cell and determines most of the channel's properties...
ion channels. Recent studies have also demonstrated that agonist-induced stimulation of the κ-Opioid receptor, like other G-protein coupled receptors, can result in the activation of mitogen-activated protein kinases (MAPK). These include extracellular signal-regulated kinase, p38 MAP kinases, and c-Jun N-terminal kinases
C-Jun N-terminal kinases
c-Jun N-terminal kinases , were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet...
.
Ligands
The synthetic alkaloid ketazocineKetazocine
Ketazocine , also known as ketocyclazocine, is a benzomorphan derivative used in opioid receptor research. Ketocyclazocine is an exogenous opioid that binds to the kappa opioid receptor....
and terpenoid natural product salvinorin A
Salvinorin A
Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans...
are potent and selective κ-opioid 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...
s. The κ-opioid receptor also mediates the action of the hallucinogenic side effects of 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 such as pentazocine
Pentazocine
Pentazocine is a synthetically prepared prototypical mixed agonist-antagonist narcotic drug of the benzomorphan class of opioids used to treat moderate to moderately severe pain...
.
Agonists
- AsimadolineAsimadolineAsimadoline is a drug which acts as a peripherally selective κ-opioid agonist. Because of its poor ability to cross the blood-brain barrier, asimadoline lacks the psychotomimetic effects of centrally acting kappa agonists, and consequently has more potential for medical use, and has been...
- BremazocineBremazocineBremazocine is a κ-opioid receptor agonist related to pentazocine. It has potency and long-lasting analgesic and diuretic effects....
- ButorphanolButorphanolButorphanol is a morphinan-type synthetic opioid analgesic developed by Bristol-Myers. Brand name Stadol was recently discontinued by the manufacturer. It is now only available in its generic formulations, manufactured by Novex, Mylan, Apotex and Ben Venue Laboratories. Butorphanol is most...
- BRL-52537BRL-52537BRL-52537 is a drug which acts as a potent and highly selective κ-opioid agonist. It has neuroprotective effects in animal studies, and is used for research into potential treatments for stroke and heart attack as well as more general brain research....
- CyclazocineCyclazocineCyclazocine is a mixed opioid agonist/antagonist related to dezocine, pentazocine and phenazocine. This family of opioid drugs is called the benzomorphans or benzazocines.- Use :...
- DextromethorphanDextromethorphanDextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
- DynorphinDynorphinDynorphins 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...
(endogenous peptide ligand) - EnadolineEnadolineEnadoline is a drug which acts as a highly selective κ-opioid agonist.In human studies, it produced visual distortions and feelings of dissociation, reminiscent of the effects of Salvinorin A....
- GR-89696GR-89696GR-89696 is a drug which acts as a highly selective κ-opioid agonist. It shows selective effects in different animal models and it is thought it may be a subtype-selective agonist for the κ2 subtype...
- selective for κ2 subtype - HZ-2HZ-2HZ-2 is a drug which acts as a highly selective κ-opioid agonist. It is a potent analgesic with around the same potency as morphine, with a long duration of action and high oral bioavailability. Side effects include sedation, nausea and dysphoria as well as diuretic effects....
- ICI-204,448ICI-204,448ICI-204,448 is a drug which acts as a potent and periperhally selective κ-opioid agonist, with possible uses in the treatment of heart attack as well as anti-itching effects. It is used in research to distinguish centrally from peripherally mediated kappa opioid receptor effects....
- peripherally selective - ICI-199,441ICI-199,441ICI-199,441 is a drug which acts as a potent and selective κ-opioid agonist, and has analgesic effects....
- KetazocineKetazocineKetazocine , also known as ketocyclazocine, is a benzomorphan derivative used in opioid receptor research. Ketocyclazocine is an exogenous opioid that binds to the kappa opioid receptor....
- LevallorphanLevallorphanLevallorphan is a drug of the morphinan family which is used as an opioid antidote or antagonist. It acts as an antagonist on μ-opioid receptor and agonist on kappa receptors [hence called [partial agonist]], Levallorphan (Lorfan, Naloxiphan) is a drug of the morphinan family which is used as an...
- LPK-26LPK-26LPK-26 is a drug which acts as a potent and selective κ-opioid agonist, and has analgesic effects....
- highly selective - MentholMentholMenthol is an organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, which is solid at room temperature and melts slightly above. The main form of menthol occurring in nature is -menthol, which is assigned...
- NalbuphineNalbuphineNalbuphine is a semi-synthetic opioid used commercially as an analgesic under a variety of trade names, including Nubain. It is noteworthy in part for the fact that at low dosages, it is found much more effective by women than by men, and may even increase pain in men, leading to its...
- NalfurafineNalfurafineNalfurafine is a κ-opioid receptor agonist marketed as a treatment for uremic pruritus in people undergoing hemodialysis....
- NorbuprenorphineNorbuprenorphineNorbuprenorphine is the primary active metabolite of buprenorphine. Norbuprenorphine acts as a μ-opioid, δ-opioid, and nociceptin receptor full agonist, as well as a κ-opioid receptor partial agonist. Norbuprenorphine crosses the blood-brain-barrier similarly to buprenorphine and likely contributes...
- OxycodoneOxycodoneOxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...
(disputed) - PentazocinePentazocinePentazocine is a synthetically prepared prototypical mixed agonist-antagonist narcotic drug of the benzomorphan class of opioids used to treat moderate to moderately severe pain...
- Salvinorin ASalvinorin ASalvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans...
- 2-Methoxymethyl Salvinorin B2-Methoxymethyl Salvinorin B2-Methoxymethyl salvinorin B is a semi-synthetic analogue of the natural product salvinorin A which is used in scientific research. It has a longer duration of action of around 2–3 hours, compared to less than 30 minutes for salvinorin A, and has increased affinity and efficacy at the κ-opioid...
and its ethoxymethyl2-Ethoxymethyl Salvinorin B2-Ethoxymethyl salvinorin B is a semi-synthetic analogue of the natural product salvinorin A, with a longer duration of action of around 3 hours , and increased affinity and intrinsic activity at the κ-opioid receptor...
and fluoroethoxymethyl homologues - SpiradolineSpiradolineSpiradoline is a drug which acts as a highly selective κ-opioid agonist. It has analgesic, diuretic and antitussive effects, and produces subjective effects in animals similar to those of ketocyclazocine and allylnormetazocine...
- TifluadomTifluadomTifluadom is a benzodiazepine derivative with an unusual activity profile. Unlike most benzodiazepines, tifluadom has no activity as a GABAA agonist, but instead is a selective agonist for the κ-opioid receptor...
- U-50488U-50488U-50488 is a drug which acts as a highly selective κ-opioid agonist, but without any μ-opioid antagonist effects. It has analgesic, diuretic and antitussive effects, and reverses the memory impairment produced by anticholinergic drugs...
- U-69593
Antagonists
- 5'-Guanidinonaltrindole5'-Guanidinonaltrindole5'-Guanidinonaltrindole is an opioid antagonist used in scientific research which is highly selective for the κ opioid receptor. It is 5x more potent and 500 times more selective than the commonly used κ-opioid antagonist norbinaltorphimine. It has a slow onset and long duration of action, and...
- BuprenorphineBuprenorphineBuprenorphine is a semi-synthetic opioid that is used...
- NorbinaltorphimineNorbinaltorphimineNorbinaltorphimine is an opioid antagonist used in scientific research. It is one of the few opioid antagonists available that is highly selective for the κ-opioid receptor, and blocks this receptor without affecting the μ- or δ-opioid receptors, although it has less selectivity in vivo than when...
- JDTicJDTicJDTic is a drug that acts as an opioid antagonist, which is highly selective for the κ-opioid receptor, and blocks this receptor without affecting the μ- or δ-opioid receptors...
Mentha spp.
Found in numerous species of mint, (including peppermintPeppermint
Peppermint is a hybrid mint, a cross between the watermint and spearmint . The plant, indigenous to Europe, is now widespread in cultivation throughout all regions of the world...
, spearmint
Spearmint
Mentha spicata syn. M. cordifolia is a species of mint native to much of Europe and southwest Asia, though its exact natural range is uncertain due to extensive early cultivation. It grows in wet soils...
, and watermint), the naturally-occurring compound Menthol
Menthol
Menthol is an organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, which is solid at room temperature and melts slightly above. The main form of menthol occurring in nature is -menthol, which is assigned...
is a weak k-opioid receptor agonist owing to its antinociceptive effects in rats. In addition, mints can desensitize a region through the activation of TRPM8
TRPM8
Transient receptor potential cation channel subfamily M member 8 , also known as the cold and menthol receptor 1 , is a protein that in humans is encoded by the TRPM8 gene.-Function:...
receptors (the 'cold'/menthol receptor).
Salvia divinorum
The key compound in Salvia divinorumSalvia divinorum
Salvia divinorum is a psychoactive plant which can induce dissociative effects and is a potent producer of "visions" and other hallucinatory experiences...
, Salvinorin A
Salvinorin A
Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans...
, is known as a non-toxic yet potent κ-opioid agonist.
Ibogaine
Used for the treatment of addiction in limited countries, ibogaine has become an icon of addiction management among certain underground circles. Despite its lack of addictive properties, ibogaine is listed as a Schedule I compound in the US, hence it is considered illegal to possess under any circumstances. Ibogaine is also a κ-opioid agonist and this property may contribute to the drug's anti-addictive efficacy.Role in treatment of drug addiction
κ-Opioid agonists have recently been investigated for their therapeutic potential in the treatment of addiction and evidence points towards dynorphin, the endogenous κ-opioid agonist, to be the body's natural addiction control mechanism. Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the μ- and κ-opioid systems. In experimental "addiction" models the κ-opioid receptor has also been shown to influence stress-induced relapse to drug seeking behavior. For the drug dependent individual, risk of relapse is a major obstacle to becoming drug free. Recent reports demonstrated that κ-opioid receptors are required for stress-induced reinstatement of cocaine seeking.One area of the brain most strongly associated with addiction is 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...
(NAcc) and 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...
while other structures that project to and from the NAcc also play a critical role. Though many other changes occur, addiction is often characterized by the reduction of dopamine D2 receptors
Dopamine receptor D2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity...
in the NAcc. In addition to low NAcc D2 binding, cocaine is also known to produce a variety of changes to the primate brain such as increases prodynorphin mRNA in caudate putamen (striatum) and decreases of the same in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
while the administration of a κ-opioid agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.
Additionally, while cocaine overdose victims showed a large increase in κ-opioid receptors (doubled) in the NAcc, κ-opioid agonist administration is shown to be effective in decreasing cocaine seeking and self-administration. Furthermore, while cocaine abuse is associated with lowered prolactin response, κ-opioid activation causes a release in prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
, a hormone known for its important role in learning, neuronal plasticity and myelination.
It has also been reported that the κ-opioid system is critical for stress-induced drug-seeking. In animal models, stress has been demonstrated to potentiate cocaine reward behavior in a kappa opioid-dependent manner. These effects are likely caused by stress-induced drug craving that requires activation of the κ-opioid system. Although seemingly paradoxical, it is well known that drug taking results in a change from homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
to allostasis
Allostasis
Allostasis is the process of achieving stability, or homeostasis, through physiological or behavioral change. This can be carried out by means of alteration in HPA axis hormones, the autonomic nervous system, cytokines, or a number of other systems, and is generally adaptive in the short term...
. It has been suggested that withdrawal-induced dysphoria or stress-induced dysphoria may act as a driving force by which the individual seeks alleviation via drug taking The rewarding properties of drug are altered, and it is clear κ-opioid activation following stress modulates the valence of drug to increase its rewarding properties and cause potentiation of reward behavior, or reinstatement to drug seeking. The stress-induced activation of κ-opioid receptors is likely due to multiple signaling mechanisms. The effects of κ-opioid agonism on dopamine systems are well documented, and recent work also implicates the mitogen-activated protein kinase cascade and pCREB in κ-opioid dependent behaviors.
Though cocaine abuse is a frequently used model of addiction, κ-opioid agonists have very marked effects on all types of addiction including alcohol and opiate abuse. Not only are genetic differences in dynorphin receptor expression a marker for alcohol dependence but a single dose of a κ-opioid antagonist markedly increased alcohol consumption in lab animals. There are numerous studies that reflect a reduction in self-administration of alcohol, and heroin dependence has also been shown to be effectively treated with κ-opioid agonism by reducing the immediate rewarding effects and by causing the curative effect of up-regulation of μ-opioid receptors that have been down-regulated during opioid abuse.
The anti-rewarding properties of κ-opioid agonists are mediated through both long-term and short-term effects. The immediate effect of κ-opioid agonism leads to reduction of dopamine release in the NAcc during self administration of cocaine and over the long term up-regulates receptors that have been down-regulated during substance abuse such as μ-opioid and D2 receptors. These receptors modulate the release of other neurochemical
Neurochemical
A neurochemical is an organic molecule, such as serotonin, dopamine, or nerve growth factor, that participates in neural activity. The science of neurochemistry studies the functions of neurochemicals.-Prominent neurochemicals:...
s such as serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
in the case of μ-opioid receptor agonists and acetylcholine in the case of D2. These changes can account for the physical and psychological remission of the pathology of addiction. The longer effects of κ-opioid agonism (30 minutes or greater) have been linked to κ-opioid receptor-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by κ-opioid-dependent modulation of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, or norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and/or via activation of downstream signal transduction pathways.
Interactions
The κ-opioid receptor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Sodium-hydrogen antiporter 3 regulator 1
Sodium-hydrogen antiporter 3 regulator 1
Sodium-hydrogen antiporter 3 regulator 1 is a regulator of Sodium-hydrogen antiporter 3. It is encoded by the gene SLC9A3R1. It is also known as ERM Binding Protein 50 or Na+/H+ Exchanger Regulatory Factor...
and Ubiquitin C
Ubiquitin C
Ubiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...
.