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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).

Discovery Edit

By the mid-1960's, it had become apparent from pharmacologic studies that opiate drugs were likely to exert their actions at specific receptor sites, and that there were likely to be multiple such sites.[1] 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.[2] 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.[3] That study has been widely credited as the first definitive finding of an opioid receptor, although two other studies followed shortly after.[4][5]


Types of receptorsEdit

There are four major subtypes of opioid receptors:[6] 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).

Receptor Subtypes Location[7] Function [7]
delta (δ)
OP1 (I)
δ1, δ2
kappa (κ)
OP2 (I)
κ1, κ2, κ3
mu (μ)
OP3 (I)
μ1, μ2, μ3 μ1:

μ2:

Nociceptin receptor
OP4
ORL1
  • anxiety
  • depression
  • appetite
  • development of tolerance to μ agonists


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).

(I). Name based on order of discovery

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, thus turning the 'm' to μ. Similarly a drug known as ketocyclazocine was first shown to attach itself to kappa receptors,[8] while the delta receptor was named after the mouse vas deferens tissue in which the receptor was first characterised.[9] 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 (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 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.[10]

An IUPHAR subcommittee[11][12] 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.



The μ-opioid receptorEdit

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 receptorEdit

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 receptorEdit

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)Edit

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 receptorEdit

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.

Additional receptorsEdit

Sigma receptors (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. allylnormetazocine), 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.[13][14][15] 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).[16][17]

Another putative opioid receptor is the epsilon (ε) opioid receptor. The existence of this receptor was suspected after the endogenous opioid peptide beta-endorphin was shown to produce additional actions which did not seem to be mediated through any of the known opioid receptors.[18][19] 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),[20] while buprenorphine has been shown to act as an epsilon antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor,[21][22] 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,[23] suggesting the epsilon receptor is likely to be a splice variant or hetero-oligomer derived from alternate post-translational modification of one or more of the known opioid receptors.

See also Edit

ReferencesEdit

  1. Martin WR (December 1967). Opioid antagonists. Pharmacol. Rev. 19 (4): 463–521.
  2. Goldstein A, Lowney LI, Pal BK (August 1971). Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain. Proc. Natl. Acad. Sci. U.S.A. 68 (8): 1742–7.
  3. Pert CB, Snyder SH (March 1973). Opiate receptor: demonstration in nervous tissue. Science (journal) 179 (77): 1011–4.
  4. Terenius L (1973). Stereospecific interaction between narcotic analgesics and a synaptic plasm a membrane fraction of rat cerebral cortex. Acta Pharmacol. Toxicol. (Copenh.) 32 (3): 317–20.
  5. Simon EJ, Hiller JM, Edelman I (July 1973). Stereospecific binding of the potent narcotic analgesic (3H) Etorphine to rat-brain homogenate. Proc. Natl. Acad. Sci. U.S.A. 70 (7): 1947–9.
  6. Corbett AD, Henderson G, McKnight AT, Paterson SJ (2006). 75 years of opioid research: the exciting but vain quest for the Holy Grail. Br. J. Pharmacol. 147 Suppl 1: S153–62.
  7. 7.0 7.1 Fine, Perry G.; Russell K. Portenoy (2004). "Chapter 2: The Endogenous Opioid System" A Clinical Guide to Opioid Analgesia, McGraw Hill.
  8. Anil Aggrawal. Opium: the king of narcotics. BLTC Research. URL accessed on 2008-03-21.
  9. Lord JA, Waterfield AA, Hughes J, Kosterlitz HW. Nature. 1977; 267:495–499.
  10. Lemke, Thomas L.; Williams, David H.; Foye, William O. (2002). "Opioid Analgesics; Fries, DS" Foye's principles of medicinal chemistry, Hagerstown, MD: Lippincott Williams & Wilkins.
  11. Girdlestone, D (October 2000). "Opioid receptors; Cox BM, Chavkin C, Christie MJ, Civelli O, Evans C, Hamon MD, et al" The IUPHAR Compendium of Receptor Characterization and Classification, 2nd Edition, 321–333, London: IUPHAR Media.
  12. "Opioid receptors". IUPHAR Database. International Union of Pharmacology (2008-08-01).
  13. Grevel J, Yu V, Sadée W (May 1985). Characterization of a labile naloxone binding site (lambda site) in rat brain. J. Neurochem. 44 (5): 1647–56.
  14. Mizoguchi H, Narita M, Nagase H, Tseng LF (October 2000). Activation of G-proteins in the mouse pons/medulla by beta-endorphin is mediated by the stimulation of mu- and putative epsilon-receptors. Life Sci. 67 (22): 2733–43.
  15. Wollemann M, Benyhe S (June 2004). Non-opioid actions of opioid peptides. Life Sci. 75 (3): 257–70.
  16. Zagon IS, Verderame MF, Allen SS, McLaughlin PJ (February 2000). Cloning, sequencing, chromosomal location, and function of cDNAs encoding an opioid growth factor receptor (OGFr) in humans. Brain Res. 856 (1-2): 75–83.
  17. Zagon IS, Verderame MF, McLaughlin PJ (February 2002). The biology of the opioid growth factor receptor (OGFr). Brain Res. Brain Res. Rev. 38 (3): 351–76.
  18. Wüster M, Schulz R, Herz A (December 1979). Specificity of opioids towards the mu-, delta- and epsilon-opiate receptors. Neurosci. Lett. 15 (2-3): 193–8.
  19. Schulz R, Wüster M, Herz A (March 1981). Pharmacological characterization of the epsilon-opiate receptor. J. Pharmacol. Exp. Ther. 216 (3): 604–6.
  20. Narita M, Tseng LF (March 1998). Evidence for the existence of the beta-endorphin-sensitive "epsilon-opioid receptor" in the brain: the mechanisms of epsilon-mediated antinociception. Jpn. J. Pharmacol. 76 (3): 233–53.
  21. Fujii H, Narita M, Mizoguchi H, Murachi M, Tanaka T, Kawai K, Tseng LF, Nagase H (August 2004). Drug design and synthesis of epsilon opioid receptor agonist: 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821) inducing antinociception mediated by putative epsilon opioid receptor. Bioorg. Med. Chem. 12 (15): 4133–45.
  22. Fujii H, Nagase H (2006). Rational drug design of selective epsilon opioid receptor agonist TAN-821 and antagonist TAN-1014. Curr. Med. Chem. 13 (10): 1109–18.
  23. Contet C, Matifas A, Kieffer BL (May 2004). No evidence for G-protein-coupled epsilon receptor in the brain of triple opioid receptor knockout mouse. Eur. J. Pharmacol. 492 (2-3): 131–6.

Further readingEdit

  • 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.

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