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Opioid receptor

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

Types of receptors

There are three major subtypes of opioid receptors: μ (mu), κ (kappa), and δ (delta). The receptors were named using the first letter of the first ligand 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 so they converted the 'm' to μ. Similarly a drug known as Ketocyclazocine was first shown to attach itself to kappa receptors [1].An alternative classification system is based on their order of discovery the receptors being termed OP1 (δ), OP2 (κ), and OP3 (μ).

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 protein binds to the third intracellular loop of the opioid receptors. Both in mice and humans the genes for the various receptor subtypes are located on different chromosomes.

Separate subtypes (μ1, μ2; κ1, κ2, κ3; δ1, δ2) 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 (Fries, 2002).

The μ-opioid receptor

The μ-receptors exist mostly presynaptically in the periaqueductal gray region, and in the superficial dorsal horn of the spinal cord. Other areas where μ-receptors have been located include the external plexiform layer of the olfactory bulb, the nucleus accumbens, in several layers of the cerebral cortex and in some of the nuclei of the amygdala. The μ-receptor has high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. Opioid alkaloids such as morphine, codeine, and methadone also bind to the μ-receptor.

Activation of the μ receptor by an agonist such as morphine causes analgesia, sedation, reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation. Some of these effects, such as sedation, euphoria and decreased respiration, tend to disappear with continued use as tolerance develops. Analgesia, miosis and reduced bowel motility tend to persist; little tolerance develops to these effects. Tolerance developes to different effects at different rates largely because these effects are caused by activation of different μ-receptor subtypes . Stimulation of μ1-receptors blocks pain while stimulation of μ2-receptor causes respiratory depression and constipation [2].

Although tolerance to respiratory depression develops relatively quickly, it is the single most adverse side effect of opioid use; it is how overdoses kill. Opioid overdoses can be rapidly reversed with any of several opioid antagonists, drugs that bind to the μ receptors more strongly than most agonists but do not activate them. This displaces the agonist drug, countering its effects.

The κ-opioid receptor

κ-Opioid receptors are also involved with analgesia, but activation also produces marked nausea and dysphoria. The endogenous ligands (naturally occurring substances which activate the receptor) are the dynorphins. κ receptors are located in the periphery by pain neurons, in the spinal cord and in the brain. Some κ-Opioid receptor agonists, such as salvinorin A have been found to be hallucinogenic although in different way than other hallucinogens such as LSD [3].

The δ-opioid receptor

δ-Opioid receptor activation also produces analgesia. Some research suggests that they may also be related to seizures. The endogenous ligands for the δ receptor are the enkephalins. Until quite recently, there were few pharmacological tools for the study of δ receptors. As a consequence, our understanding of their function is much more limited than those of the other opioid receptors.

The orphan opioid receptor (ORL 1)

An additional opioid receptor has been identified and cloned based on homology with the cDNA. This receptor is known as the ORL 1 receptor. It's natural ligand is known alternately as nociceptin or orphanin. Nociceptin is thought to be an endogenous antagonist of dopamine transport that may act either directly on dopamine or by inhibiting GABA to effect dopamine levels [4]. Within the central nervous system its action can be either similar or opposite to those of opioids depending on their location [5]. It controls a wide range of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites[6].

ORL 1 agonists are being studied as treatments for heart failure and migraine [7] while nociceptin antagonists may have antidepressant qualities [8]. The novel drug buprenorphine is a partial agonist at ORL 1 receptors while its metabolite norbuprenorphine is a full agonist at these receptors [9].

The σ receptor

The sigma receptors σ1 and σ2 were once thought to be a type of opioid receptor, because the d stereoisomers of the benzomorphan class of opioid drugs had no effects at σ, σ, and σ receptors, but reduced coughing. However, pharmacological testing indicated that the sigma receptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors. When the σ1 receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors. At this point, they were designated as a separate class of receptors.


  • Fries, DS (2002). Opioid Analgesics. In Williams DA, Lemke TL. Foye's Principles of Medicinal Chemistry (5 ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 0-683-30737-1.
  • Henderson G, McKnight AT (1997). The orphan opioid receptor and its endogenous ligand - nociceptin/orphanin FQ. Trends Pharmacol Sci 18, 293-300.

See also

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